Objectives. Emerging evidence indicates that tendon disease is an active process with inflammation that is critical to disease onset and progression. However, the key cytokines responsible for driving and sustaining inflammation have not been identified. Methods. We performed a systematic review of the literature using MEDLINE (U.S. National Library of Medicine, Bethesda, Maryland) in March 2017. Studies reporting the expression of interleukins (ILs), tumour necrosis factor alpha (TNF-α) and interferon gamma in diseased human tendon tissues, and animal models of tendon injury or exercise in comparison with healthy control tissues were included. Results. IL-1β, IL-6, IL-10, and TNF-α are the cytokines that have been most frequently investigated. In clinical samples of tendinopathy and tendon tears, the expression of TNF-α tended not to change but IL-6 increased in tears. Healthy human tendons showed increased IL-6 expression after exercise; however, IL-10 remained unchanged. Animal tendon injury models showed that IL-1β, IL-6, and TNF-α tend to increase from the early phase of tendon healing. In animal exercise studies, IL-1β expression showed a tendency to increase at the early stage after exercise, but IL-10 expression remained unchanged with exercise. Conclusions. This review highlights the roles of IL-1β, IL-6, IL-10, and TNF-α in the development of tendon disease, during tendon healing, and in response to exercise. However, there is evidence accumulating that suggests that other cytokines are also contributing to tendon inflammatory processes. Further work with hypothesis-free methods is warranted in order to identify the key cytokines, with subsequent mechanistic and interaction studies to elucidate their roles in tendon disease development. Cite this article: W. Morita, S. G. Dakin, S. J. B. Snelling, A. J. Carr. Cytokines in tendon disease: A Systematic Review. Bone Joint Res 2017;6:656–664. DOI: 10.1302/2046-3758.612.BJR-2017-0112.R1

The two main categories of tendo Achillis tendon disorder are broadly classified by anatomical location to include non-insertional and insertional conditions. Non-insertional Achilles tendinopathy is often managed conservatively, and many rehabilitation protocols have been adapted and modified, with excellent clinical results. Emerging and popular alternative therapies, including a variety of injections and extracorporeal shockwave therapy, are often combined with rehabilitation protocols. Surgical approaches have developed, with minimally invasive procedures proving popular. The management of insertional Achilles tendinopathy is improved by recognising coexisting pathologies around the insertion. Conservative rehabilitation protocols as used in non-insertional disorders are thought to prove less successful, but such methods are being modified, with improving results. Treatment such as shockwave therapy is also proving successful. Surgical approaches specific to the diagnosis are constantly evolving, and good results have been achieved

The rotator cuff tendinopathy is one of the most common shoulder problems leading to full-thickness rotator cuff tendon tear and, eventually, to degenerative arthritis. Recent research on rotator cuff tendon degeneration has focused on its relationship to cell death. The types of cell death known to be associated with rotator cuff tendon degeneration are apoptosis, necrosis, and autophagic cell death. The increased incidence of cell death in degenerative tendon tissue may affect the rates of collagen synthesis and repair, possibly weakening tendon tissue and increasing the risk of tendon rupture. The biomolecular mechanisms of the degenerative changes leading to apoptotic cell death in rotator cuff tenofibroblasts have been identified as oxidative-stress-related cascade mechanisms. Furthermore, apoptosis, necrosis, and autophagic cell death are all known to be mediated by oxidative stress, a condition in which ROS (reactive oxygen species) are overproduced. Lower levels of oxidative stress trigger apoptosis; higher levels mediate necrosis. Although the signaltransduction pathway leading to autophagy has not yet been fully established, ROS are known to be essential to autophagy. A neuronal theory regarding rotator cuff degeneration has been developed from the findings that glutamate, a neural transmitter, is present in increased concentrations in tendon tissues with tendinopathy and that it induces rat supraspinatus tendon cell death. Recent studies have reported that hypoxia involved in rotator cuff tendon degeneration. Because antioxidants are known to scavenge for intracellular ROS, some studies have been conducted to determine whether antioxidants can reduce cell death in rotator cuff tendon-origin fibroblasts. The first study reported that an antioxidant has the ability to reduce apoptosis in oxidative-stressed rotator cuff tenofibroblasts. The second study reported that antioxidants have both antiapoptotic effects and antinecrotic effects on rotator cuff tendon-origin fibroblasts exposed to an oxidative stimulus. The third study reported that an antioxidant has antiautophagic-cell-death effects on rotator cuff tendon-origin fibroblasts exposed to an oxidative stimulus. The fourth study reported that glutamate markedly increases cell death in rotator cuff tendonorigin fibroblasts. The glutamate-induced cytotoxic effects were reduced by an antioxidant, demonstrating its cytoprotective effects against glutamate-induced tenofibroblast cell death. The fifth study reported that hypoxia significantly increases intracellular ROS and apoptosis. The hypoxia-induced cytotoxic effects were markedly attenuated by antioxidants, demonstrating their cytoprotective effects against hypoxia-induced tenofibroblast cell death. In conclusion, antioxidants have cytoprotective effects on tenofibroblasts exposed in vitro to an oxidative stressor, a neurotransmitter, or hypoxia. These cytoprotective effects result from antiapoptotic, antinecrotic, and antiautophagic actions involving the inhibition of ROS formation. These findings suggest that antioxidants may have therapeutic potential for rotator cuff tendinopathy. Further studies must be conducted in order to apply these in vitro findings to clinical situations

Aims. In the context of tendon degenerative disorders, the need for innovative conservative treatments that can improve the intrinsic healing potential of tendon tissue is progressively increasing. In this study, the role of pulsed electromagnetic fields (PEMFs) in improving the tendon healing process was evaluated in a rat model of collagenase-induced Achilles tendinopathy. Methods. A total of 68 Sprague Dawley rats received a single injection of type I collagenase in Achilles tendons to induce the tendinopathy and then were daily exposed to PEMFs (1.5 mT and 75 Hz) for up to 14 days - starting 1, 7, or 15 days after the injection - to identify the best treatment option with respect to the phase of the disease. Then, 7 and 14 days of PEMF exposure were compared to identify the most effective protocol. Results. The daily exposure to PEMFs generally provided an improvement in the fibre organization, a decrease in cell density, vascularity, and fat deposition, and a restoration of the physiological cell morphology compared to untreated tendons. These improvements were more evident when the tendons were exposed to PEMFs during the mid-acute phase of the pathology (7 days after induction) rather than during the early (1 day after induction) or the late acute phase (15 days after induction). Moreover, the exposure to PEMFs for 14 days during the mid-acute phase was more effective than for 7 days. Conclusion. PEMFs exerted a positive role in the tendon healing process, thus representing a promising conservative treatment for tendinopathy, although further investigations regarding the clinical evaluation are needed. Cite this article: Bone Joint Res 2020;9(9):613–622

The prevalence of gluteal tendinopathy (GT) associated with osteoarthritis of the hip is difficult to determine as it is frequently undiagnosed or misdiagnosed as trochanteric bursitis. Its relationship to total hip arthroplasty (THA) outcomes is currently unknown. The aim of this study was to determine the incidence of GT at the time of hip arthroplasty and examine the relationship between GT and patient reported outcomes (PROMS) before and after THA. Patients undergoing THA for primary osteoarthritis between August 2017 and August 2020 were recruited. Tendinopathy was assessed and graded at time of surgery. PROMS included the Oxford Hip Score (OHS), HOOS JR, EQ-5D, and were collected preoperatively and at one year after THA. Satisfaction with surgery was also assessed at 1 year. 797 patients met eligibility criteria and were graded as Grade 1: normal tendons (n =496, 62%), Grade 2: gluteal tendinopathy but no tear (n=222, 28%), Grade 3: partial/full thickness tears or bare trochanter (n=79, 10%). Patients with abnormal gluteal tendons were older (p=0.001), had a higher mean BMI (p=0.01), and were predominately female (p=0.001). Patients with higher grade tendinopathy had statistically significant inferior PROMS at one year, OHS score (44.1 v 42.9 v 41.3, p 0.001) HOOS JR (89.3 V 86.3 V 85.6 p 0.005). Increasing gluteal tendon grade was associated with a greater incidence of problems with mobility (p=0.001), usual activities (p=0.001) and pain (p=0.021) on EQ5D. There was a 3 times relative risk of overall dissatisfaction with THA in the presence of gluteal tears. This study demonstrated that gluteal tendinopathy was commonly observed and associated with inferior 1-year PROMS in patients undergoing THA for OA. Increasing degree of tendinopathy was a negative prognostic factor for worse functional outcomes and patient satisfaction

Stem cells represent an exciting biological therapy for the management of many musculoskeletal tissues that suffer degenerative disease and/or where the reparative process results in non-functional tissue (‘failed healing’). The original hypothesis was that implanted cells would differentiate into the target tissue cell type and synthesise new matrix. However, this has been little evidence that this happens in live animals compared to the laboratory, and more recent theories have focussed on the immunomodulatory effects via the release of paracrine factors that can still improve the outcome, especially since inflammation is now considered one of the central processes that drive poor tendon healing. Because of the initial ‘soft’ regulatory environment for the use of stem cells in domestic mammals, bone and fat-derived stem cells quickly established themselves as a useful treatment for naturally occurring musculoskeletal diseases in the horse more than 20 years ago (Smith, Korda et al. 2003). Since the tendinopathy in the horse has many similarities to human tendinopathy, we propose that the following challenges and, the lessons learnt, in this journey are highly relevant to the development of stem cells therapies for human tendinopathy:. Source – while MSCs can be recovered from many tissues, the predominant sources for autologous MSCs have been bone and fat. Other sources, including blood, amnion, synovium, and dental pulp have also been commercialised for allogenic treatments. Preparation – ex vivo culture requires transport from a licensed laboratory while ‘minimally manipulated’ preparations can be prepared patient-side. Cells also need a vehicle for transport and implantation. Delivery – transport of cells from the laboratory to the clinic for autologous ex vivo culture techniques; implantation technique (usually by ultrasound-guided injection to minimise damage to the cells (or, more rarely, incorporated into a scaffold). They can also be delivered by regional perfusion via venous or arterial routes. Retention – relatively poor although small numbers of cells do survive for at least 5 months. Immediate loss to the lungs if the cells are administered via vascular routes. Synovially administered cells do not engraft into tendon. Adverse effects – very safe although needle tracts often visible (but do not seen to adversely affect the outcome). Allogenic cells require careful characterisation for MHC Class II antigens to avoid anaphylaxis or reduced efficacy. Appropriate injuries to treat – requires a contained lesion when administered via intra-lesional injection. Intrasynovial tendon lesions are more often associated with surface defects and are therefore less appropriate for treatment. Earlier treatment appears to be more effective than delayed, when implantation by injection is more challenging. Efficacy - beneficial effects shown at both tissue and whole animal (clinical outcome) level in naturally-occurring equine tendinopathy using bone marrow-derived autologous MSCs Recent (licenced) allogenic MSC treatment has shown equivalent efficacy while intra-synovial administration of MSCs is ineffective for open intra-synovial tendon lesions. Regulatory hurdles – these have been lighter for veterinary treatments which has facilitated their development. There has been greater regulation of commercial allogenic MSC preparations which have required EMA marketing authorisation

Tendinopathy is one of the most common orthopaedic pathological conditions characterized by tendon degenerative changes. Excessive mechanical loading is considered as a major causative factor in the development of tendinopathy, but the mechanisms of pathogenesis remain unclear. High mobility group box-1 (HMGB1), a potent inflammatory mediator when released into the matrix, has been identified in the early stage tendinopathy patients. Since the release and contribution of HMGB1 in tendinopathy development due to mechanical overloading is unknown, we investigated the role of HMGB1 in tendinopathy using a mouse intensive treadmill running (ITR) model and injection of glycyrrhizin (GL), a specific inhibitor of HMGB1. A total of 48 mice were divided into four groups, Cage Control group: The animals were allowed to move freely in their cage, GL group: The animals were received daily IP injection of GL (50 mg/kg body weight) for 24 weeks, ITR group: The animals ran on treadmill at 15 meters/min for three h/ day, five days a week for 12 or 24 weeks, GL+ITR group: The animals ran the same protocol as that of ITR group plus daily IP injection of GL for 12 or 24 weeks. Six mice/group were sacrificed at 12 or 24 weeks and the Achilles and patellar tendon tissues were harvested and used for histochemical staining and immunostaining. Mechanical overloading induced HMGB1 released from the cell nuclei to the matrix (Fig. 1a, b) caused tendon inflammation (Fig. 1c, d) and led to tendon degenerative changes (Fig. 1e-j). After 12 weeks of ITR, the tendon tissue near the bone insertion site showed typical tendinopathic changes in cell shape, accumulation of glycosaminoglycans (GAG) (Fig. 1e, f), and increase in SOX-9 staining (Fig. 1g-j). After 24 weeks ITR, the distal site of Achilles tendon showed considerable changes in cell shape (Fig. 2A, g, arrows), which is round compared to more elongated in the control and GL groups (Fig. 2A, e, f). However, daily treatment with GL prior to ITR blocked the cell shape change (Fig. 2A, h) and, ITR induced extensive GAG accumulation in ITR group (Fig. 2B, bottom panel). Furthermore, GL inhibited ITR-induced expression of chondrogenic markers (SOX-9 and collagen II) in the tendons (Fig. 3). Our results showed that mechanical overloading-induced HMGB1 plays a critical role in the development of tendinopathy by initiating tendon inflammation and eventual degeneration characterized by the presence of chondrocyte-like cells, accumulation of proteoglycans, high levels of collagen type II production, and chondrogenic marker SOX-9 expression. These results provide the first evidence for the role of HMGB1 as a therapeutic target to prevent tendinopathy before its onset and block further development at its early inflammation stages. The inhibition of tendinopathy development by GL administration in this study also suggests the putative therapeutic potential of this natural triterpene that is already in clinical use to treat other inflammation-related diseases. For any figures or tables, please contact authors directly

Adipose tissue releases several bioactive peptides and hormones, like adipokines that promote a low inflammatory systemic state. Inflammation, affecting the tendon homeostasis, could play a role in tendon disease development as well as in the healing process. Obese patients show a dysregulated level of adipokines and considering the higher mechanical demand, this relates to higher incidence of tendinopathies among these subjects. A systematic review was performed searching PubMed, Embase and Cochrane Library databases. Inclusion criteria were studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results. Evaluated data were extracted and critically analysed. PRISMA guidelines were applied, and risk of bias was assessed, as was the methodological quality of the included studies. We excluded all the articles with high risk of bias and/or low quality after the assessment. After applying the previously described criteria, we included 12 articles assessed as medium or high quality. Leptin, others adipokines and in general changes in the hormones delicate equilibrium affect the tendon either qualitatively and/or quantitatively. The evidence still lacks consensus on their role which is probably involved in both anabolic and catabolic pathways. The role of adipokines in the structure and healing of tendons is still debated. Further studies are needed to clarify the relation between deregulated levels of adipokines and the development of tendinopathy. A better understanding of the molecular interactions could allow us to individuate future therapeutic targets

The role of inflammatory cells and their products in tendinopathy is not completely understood. Pro-inflammatory cytokines are upregulated after oxidative and other forms of stress. Based on observations that increased cytokine expression has been demonstrated in cyclically-loaded tendon cells we hypothesised that because of their role in oxidative stress and apoptosis, pro-inflammatory cytokines may be present in rodent and human models of tendinopathy. A rat supraspinatus tendinopathy model produced by running overuse was investigated at the genetic level by custom micro-arrays. Additionally, samples of torn supraspinatus tendon and matched intact subscapularis tendon were collected from patients undergoing arthroscopic shoulder surgery for rotator-cuff tears and control samples of subscapularis tendon from ten patients with normal rotator cuffs undergoing arthroscopic stabilisation of the shoulder were also obtained. These were all evaluated using semiquantitative reverse transcription polymerase chain-reaction and immunohistochemistry. We identified significant upregulation of pro-inflammatory cytokines and apoptotic genes in the rodent model (p = 0.005). We further confirmed significantly increased levels of cytokine and apoptotic genes in human supraspinatus and subscapularis tendon harvested from patients with rotator cuff tears (p = 0.0008). These findings suggest that pro-inflammatory cytokines may play a role in tendinopathy and may provide a target for preventing tendinopathies

Aims. Rotator cuff tendinopathy has a multifactorial origin. Rejecting the mechanistic theory has also led to abandoning operative treatment at initial presentation in the first line. Physiotherapy exercise programmes are the accepted first line treatment. The aim of this study was to assess the long-term additional benefits of subacromial decompression in the treatment of rotator cuff tendinopathy. Patients and Methods. This randomised controlled trial of 140 patients (52 men, 88 women, mean age 47.1 years; 18 to 60) with rotator cuff tendinopathy extended previous work up to a maximum of 13 years. The patients were randomised into two treatment groups: arthroscopic acromioplasty and a supervised exercise treatment and a similar supervised exercise treatment alone. Self-reported pain on a visual analogue scale (VAS) was the primary outcome measure. Secondary measures were disability, working ability, pain at night, Shoulder Disability Questionnaire score and the number of painful days during the three months preceding the final assessment. Results. A total of 90 patients (64%) returned questionnaires at a mean 12 years after randomisation. On an intention-to-treat basis, both treatment groups reached statistically significant improvement compared with the initial VAS for pain, but there was no significant difference between groups. The same was true in the secondary outcome measures. Due to group changes, the results were also analysed per protocol: operated or not. No significant differences between the groups were found. Conclusion. The natural history of rotator cuff tendinopathy probably plays a significant role in the results in the long-term. Even though the patients who underwent operative treatment had a stronger belief in recovery, which is likely to be surgical and the effect of placebo, the exercise group obtained similar results. In the future, an optimum exercise regime should be searched for, as the most clinically and cost-effective conservative treatment for rotator cuff tendinopathy. Cite this article: Bone Joint J 2017;99-B:799–805

Tendinopathies represent the 45% of the musculoskeletal lesions and they are a big burden in clinics. Indeed, despite the relevant social impact, both the pathogenesis and the development of the tendinopathy are still under-investigated, thus limiting the therapeutic advancement in this field. Indeed, current treatment for tendinopathy are mainly symptomatic, and they present a high rate of pathology re-occurrence. In this contest, the development of an efficient in vivo model of acute tendinopathy, focused on the choice of the most appropriate species and strategy to induce the disease, would allow a better understanding of the pathology progression throughout its phases. Then, the purpose of this study was to evaluate the dose-dependent and time-related tissue-level changes occurring in a collagenase-induced tendinopathy in rat Achilles tendons, in order to establish a standardized model for future pre-clinical studies. 40 Sprague Dawley rats were randomly divided into two groups, treated by injection of collagenase type I within the Achilles tendon at 1 mg/mL (low dose, LD) or 3 mg/mL (high dose, HD). Tendon explants were histologically evaluated at 3, 7, 15, 30 and 45 days by H&E staining. Our results showed that both the collagenase doses induced a disorganization of collagen fibers and increased the number of rounded resident cells. In particular, the high dose treatment determined a greater fatty degeneration and neovascularization with respect to the lower dose. These changes are time-dependent, thus resembling the tendinopathy development in humans. Indeed, the acute phase occurred from day 3 to day 15, while from day 15 to 45 it progressed towards the proliferative phase, displaying a degenerative appearance associated with a precocious remodeling process. The model represents a good balance between feasibility, in terms of reproducibility and costs, and similarity with the human disease. Moreover, the present model contributes to improve the knowledge about tendinopathy development, and then it could be useful to design further pre-clinical studies, in particular in order to test innovative treatments for tendinopathy

Achilles tendinopathy is a common cause of disability. Despite the economic and social relevance of the problem, the causes and mechanisms of Achilles tendinopathy remain unclear. Tendon vascularity, gastrocnemius-soleus dysfunction, age, gender, body weight and height, pes cavus, and lateral ankle instability are considered common intrinsic factors. The essence of Achilles tendinopathy is a failed healing response, with haphazard proliferation of tenocytes, some evidence of degeneration in tendon cells and disruption of collagen fibres, and subsequent increase in non-collagenous matrix. Tendinopathic tendons have an increased rate of matrix remodelling, leading to a mechanically less stable tendon which is more susceptible to damage. The diagnosis of Achilles tendinopathy is mainly based on a careful history and detailed clinical examination. The latter remains the best diagnostic tool. Over the past few years, various new therapeutic options have been proposed for the management of Achilles tendinopathy. Despite the morbidity associated with Achilles tendinopathy, many of the therapeutic options described and in common use are far from scientifically based. New minimally invasive techniques of stripping of neovessels from the Kager's triangle of the tendo Achillis have been described, and seem to allow faster recovery and accelerated return to sports, rather than open surgery. A genetic component has been implicated in tendinopathies of the Achilles tendon, but these studies are still at their infancy

Obese patients show a higher incidence of tendon-related pathologies. These patients present a low inflammatory systemic environment and a higher mechanical demand which can affect the tendons. In addition, inflammation might have a role in the progression of the disease as well as in the healing process. A systematic review was performed by searching PubMed, Embase and Cochrane Library databases. Inclusion criteria were studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results. Evaluated data were extracted and critically analysed. PRISMA guidelines were applied, and risk of bias was assessed, as well as the methodological quality of the included studies. We excluded all the articles with high risk of bias and/or low quality after the assessment. Due to the high heterogeneity present among the studies, a metanalysis could not be done. Thus, a descriptive analysis was performed. After applying the previously described criteria, thirty articles were included, assessed as medium or high quality. We analysed the data of 50865 subjects, 6096 of which were obese (BMI over 30 accordingly to the WHO criteria). The overall risk of re-tear after surgery is about the 10% more than normal BMI subjects. The rupture risk fluctuates in the studies without showing a significant trend. Obese subjects have a higher risk to develop tendinopathy and a worse outcome after surgery as confirmed in several human studies. The obesity influence on tendon structure and mechanical properties may rely on the fat tissue endocrine proprieties and on hormonal imbalance. Clinicians should consider obesity as a predisposing factor for the development of tendinopathies and for a higher risk of complications in patients who underwent surgical repair of tendons

Autologous tendon cell injection (ATI) is a promising non-surgical treatment for tendinopathies and tendon tear that address its underlying pathology. The procedure involves harvesting autologous tendon tissue, the isolation of the tendon cells, expansion under quality assured GMP cell laboratory and the injection of the tendon cells via U/S into the degenerative tendon tissue. In clinical practice, the patella (PT) and palmaris longus (PL) tendons are common sites used for tendon tissue biopsy. The objective of this study is to compare the tendon cell quality, identity, purity, doubling time and yield of cells between PT and PL tendons for ATI. Tendon tissue biopsies were harvested from PT via U/S using a 14-gauge needle or resected surgically from the PL tendon. The biopsies were transported to a GMP cell laboratory, where tendon cells were isolated, cultured and expanded for 4 to 6 weeks, and analysed for viability, cell doubling time, cellular characteristics including cell purity, potency and identity (PPI). Tendon samples from 149 patients were analysed (63 PT). Average biopsy weight was 62mg for PT and 119mg for PI (p<0.001). Average cell doubling time (83.9 vs 82.7 hours), cellular yield (16.2 vs 15.2x106), viability (98.7 vs 99.0%) and passage number (3 vs 3) were not significantly different between tendons. Additionally, ddPCR analyses showed no differences of PPI including tendon cell markers of collagen type I, scleraxis and tenomodulin. No post-biopsy complications or contamination were reported for either group. Assessing tendon tissue from palmaris tendon is relatively easier. Tendon tissue biopsy tissue for autologous tendon cell therapy can be obtained from either the PT or PL tendons. Tendon cells isolated from PT and PL were equal in growth characteristics and PPI. There are no differences in the quality of tendon cells isolated from the PT or PL

We conducted a randomised controlled trial to determine whether active intense pulsed light (IPL) is an effective treatment for patients with chronic mid-body Achilles tendinopathy. A total of 47 patients were randomly assigned to three weekly therapeutic or placebo IPL treatments. The primary outcome measure was the Victorian Institute of Sport Assessment – Achilles (VISA-A) score. Secondary outcomes were a visual analogue scale for pain (VAS) and the Lower Extremity Functional Scale (LEFS). Outcomes were recorded at baseline, six weeks and 12 weeks following treatment. Ultrasound assessment of the thickness of the tendon and neovascularisation were also recorded before and after treatment. . There was no significant difference between the groups for any of the outcome scores or ultrasound measurements by 12 weeks, showing no measurable benefit from treatment with IPL in patients with Achilles tendinopathy. Cite this article: Bone Joint J 2013;95-B:504–9

The cellular mechanisms of tendinopathy remain unclear, particularly with respect to the role of inflammation in early disease. We have previously identified increased levels of inflammatory cytokines in an early human model of tendinopathy and sought to extend these studies to the cellular analysis of tissue. Purpose. To characterise inflammatory cell subtypes in early human tendinopathy we explored the phenotype and quantification of inflammatory cells in torn and control tendon samples. Design. Controlled laboratory study. Methods. Torn supraspinatus tendon and matched intact subscapularis tendon samples were collected from twenty patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from ten patients undergoing arthroscopic stabilisation surgery. Tendon biopsies were evaluated immunohistochemically by quantifying the presence of macrophages (CD68 and CD206), T cells (CD3), mast cells (Mast cell tryptase) and vascular endothelium (CD34). Results. Subscapularis tendon biopsies obtained from patients with torn supraspinatus tendon exhibited significantly greater macrophage, mast cell and T cell expression compared to either torn supraspinatus samples or control subscapularis derived tissue (p< 0.01). Inflammatory cell infiltrate correlated inversely (r=0.5, p< 0.01) with rotator cuff tear size, with larger tears correlating with a marked reduction in all cell lineages. There was a modest but significant correlation between mast cells and CD 34 expression (r= 0.4, p< 0.01) in pre-rupture subscapularis tendon. Conclusion. We provide evidence for an inflammatory cell infiltrate in early mild/moderate human supraspinatus tendinopathy. In particular, we demonstrate significant infiltration of mast cells and macrophages suggesting a role for innate immune pathways in the events that mediate early tendinopathy. Further mechanistic studies to evaluate the net contribution and hence therapeutic utlity of these cellular lineages and their downstream processes may reveal novel therapeutic approaches to the management of early tendinopathy

Tendon-related pathologies such as tendinopathy represent a relevant clinical and socioeconomic issue. The most innovative and conservative therapeutic approaches are meant to stimulate the intrinsic healing capability of the tissue. In this study, the use of pulsed electromagnetic fields (PEMFs) was investigated in a rat model of Achilles tendinopathy as a potential therapy. Achilles tendinopathy was chemically induced in eighty-six Sprague Dawley rats by injecting collagenase Type I within the tendon fibers. Fifty-six of them were stimulated with PEMFs (8 hours/day, 1.5 ± 0.2 mT; 75 Hz), divided in different experimental groups basing on the starting-time of PEMFs exposure (after 0, 7, 15 after Collagenase injection) and its duration (7, 15 or 30 days). Thirty animals were left unstimulated (CTRL group). According to the different time points, explanted tendons were evaluated through histological and immunohistochemical analyses in term of matrix deposition, fiber re-organization, neovascularization and inflammatory reaction. The most effective PEMF stimulation was demonstrated in the 15 days of treatment. However, when PEMF were applied immediately after the collagenase injection, no significant therapeutic results were found. On the contrary, when PEMF were applied after 7 and 15 days from the collagenase injection, they promoted the deposition of extracellular matrix and tendon fiber re-organization, reducing both the inflammatory reaction and vascularization, with significant differences compared to the CTRL group (p<0.05). Therefore, these results suggest an effective activity of PEMFs stimulation that provides a satisfying restoration of the damaged tissue, although the most performing protocol of application still needs to be identified

Introduction: Tendinopathy entails pain and degenerative tissue proliferation such as tenocyte transformation and increased numbers of sensory nerves and microvessels. Pain and tissue proliferation are suggested to be modulated via nerve transmitters, including substance P (SP) and glutamate, both detected in tendinopathy. Substance P and glutamate are known to activate glutamate receptors in a variety of pain conditions and additionally to be implicated in cell transformation. However, the presence of different glutamate receptors, eg. ionotropic (NMDA) and metabotropic (mGlu), and whether they are up- or downregulated in tendinopathy is still unknown. In this study we assessed the. presence,. the tissue density and. the co-existence of different glutamate receptors together with glutamate in tendinopathic biopsies and controls. Methods: All procedures were conducted with local ethical committee approval and patient consent. Human patellar tendon biopsies of tendinopathic patients (n=10) and controls (n=8) were single- and double-stained immunohistochemically for glutamate, glutamate receptors NMDAR1, mGluR1, mGluR5 and mGluR6,7, the nerve marker PGP9.5 and SP and assessed subjectively and semi-quantitatively with image analysis. Images were taken using an epifluorescence microscope with camera and were subjectively assessed by two independent observers blinded with regard to the identity of the slides. Tenocyte density and morphologic characteristics were assessed. Non-parametric Mann-Whitney U-tests for independent samples were used, and the level for significance was set at p< 0.05. Results: Of the glutamate receptors tested all except mGluR1 was identified in the tendons, however only NMDAR1 was found significantly altered between both groups. The chronic painful tendons exhibited a significant elevation of NMDAR1 (9-fold) and also of glutamate (10-fold). This up-regulation of NMDAR1 and glutamate was found to be co-localized on sensory nerve fibers, blood vessels as well as on transformed tenocytes. None of the controls exhibited neuronal co-existence of glutamate with NMDAR1. Conclusions: This study establishes for the first time that patients with tendinopathy exhibit an elevation of peripheral glutamate receptor NMDAR1, morphologically co-localized with increased glutamate expression. The up-regulated NMDAR1/glutamate system may represent hyper-excitability of the cells – leading to cell proliferative effects observed as angiogenesis, tenocyte transformation, and nerve sprouting. Moreover, the neuronal co-existence of glutamate and NMDAR1 observed in painful tendinosis, but not seen in any of the controls, strongly suggests a role in pain signalling. Future studies will focuse on interventional approaches to investigate if modulation of NMDAR1 pathways can ameliorate the symptoms of tendinopathic patients

We evaluated sensitivity, specificity, reproducibility and predictive value of palpation, of the painful arc sign, and of the ‘Royal London Hospital test’ in 10 patients with Achilles tendinopathy, and in 14 asymptomatic subjects using a test-retest study design. Ten male athletes on the waiting list for exploration of one of their Achilles tendons for tendinopathy of the main body of the tenon attended a special clinic. Each was invited to bring at least one athlete of the same sex in the same discipline aged within two years of themselves, with no history and no symptoms of AT. A total of 14 controls were thus recruited. Pain and tenderness following performance of palpation, the painful arc sign, and the ‘Royal London Hospital test’ were recorded. There were no statistically significant differences at the 5% level among the effects of investigator or between morning and afternoon measurements for any of the three assessment methods. There was no evidence of a difference of the three assessment methods (p> 0.05). When the three methods were combined, the overall sensitivity was 0.586 (CI 0.469 – 0.741) and the overall specificity was 0.833 (CI 0.758 – 0.889). In patients with tendinopathy of the Achilles tendon with a tender area of intratendinous swelling which moves with the tendon and whose tenderness significantly decreases or disappears when the tendon is put under tension, a clinical diagnosis of tendinopathy can be formulated, with a high positive predictive chance that the tendon will show ultrasonographic and histological features of tendinopathy

Aim. Iliopsoas tendinopathy occurs due to friction of the iliopsoas tendon on the iliopectineal bar or the hip capsule causing pain and snapping of the hip. In adolescent cases this condition is generally treated conservatively with physiotherapy, stretching and NSAIDs. Our aim was to study the outcome of non-operative management of iliopsoas tendinopathy. Method. A retrospective 4-year study identified adolescent patients with a clinical diagnosis of psoas tendinopathy managed non-operatively. These patients were followed up by postal questionnaire, which included functional assessment using the Non-Arthritic Hip Score (NAHS). A custom study questionnaire assessed current symptoms and the effects of physiotherapy. All patients not treated conservatively were removed from the study. Results. 36 patients were treated conservatively for psoas tendinopathy. 28 completed and returned the questionnaires to a satisfactory standard. Mean NAHS was 77.72 (CI: 69.91 to 85.54) at a mean follow up of 37 months (Range: 14 to 58 months; CI 31 to 43 months). Pain was the least disabling NAHS domain at final follow up with a significant improvement over the follow up period (p<0.001). 11 patients suffered from recurrence of symptoms (clicking, stiffness, decreased range of motion). 7 patients (25%) complained of significant pain following conservative management. A Numbers Needed to Treat analysis (NNT) was performed, comparing our data with that of surgically managed patients in previously published studies. This analysis suggests that for every 6 surgical releases, 5 would have recovered anyway with non-operative management. Conclusion. Non-operative management is successful in managing psoas tendinopathy in about 75% of adolescent patients. It is especially effective in males, and patients who are more active prior to development of symptoms

Alarmins- also referred to as damage associated molecular patterns (DAMPS)- are endogenous molecules mobilized in response to tissue damage known to activate the innate immune system and regulate tissue repair and remodelling. The molecular mechanisms that regulate inflammatory and remodelling pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. S100A8 and S100A9 are low molecular weight calcium binding proteins primarily released by activated phagocytes in an inflammatory setting and also secreted as a heterodimeric complex that exhibits cytokine like functions. Based on our previous investigations we sought evidence of S100A8/A9 expression in human tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate inflammatory mediators and matrix regulation in human tenocytes. Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. S100A8/A9 expression was analysed at transcript and protein level using quantitative RT-PCR and immunohistochemistry, respectively. Primary human tenocytes were cultured from hamstring tendon tissue obtained during hamstring tendon ACL reconstruction. The in vitro effect of recombinant human S100 A8/A9 on primary human tenocytes was measured using quantitative RT-PCR and ELISA. Immunohistochemistry of tendinopathic tissues demonstrated the presence of S100 A8/A9 in diseased tissues compared to control tissue. In addition, early pathological diseased tissue indicated greater S100A9 expression compared with established diseased pathology. These findings were reflected by data obtained at transcript level from diseased tissues. Recombinant human S100A8, A9 and A8/A9 complex led to significant increase in expression of inflammatory mediators, including IL-6 in vitro. Further analysis via quantitative RT-PCR demonstrated recombinant S100A8, A9 and A8/A9 complex treatment on tenocytes, in vitro, had no direct effect on the expression of genes involved in matrix remodelling. The presence of S100A8 and S100A9 in early tendinopathic lesions suggests expression is upregulated in response to cellular damage. S100A8 and S100A9 are endogenous ligands of Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE). These receptors have known regulatory effects on immune mediated cytokine production. We propose S100A8 and S100A9 as active alarmins in the early stages of tendinopathy and thus targeting of its downstream signalling may offer novel therapeutic approaches in the management of human tendon disorders

Achilles tendinopathy is classically defined as a tendinosis devoid of an inflammatory cell population. However, recent literature suggests inflammation as a mediator in the pathogenesis. These finding were mainly based on semi-quantative immunohistochemistry. We therefore used flow cytometry to obatain a more accurate identification and quantification of the different cell types involved. Thirty-two samples were obtained from twelve patients with chronic tendinopathic lesions undergoing Achilles tendon surgery. Samples obtained from three patients with hemiplegia requiring surgical release due to spastic Achilles tendons served as control. We used two panels to identify the myeloid and lymphoid population targeting the following markers: CD45, CD3, CD8, CD4, CD19, CD11b, CD56, CD14, CD16, Vα7.2, 6b11, CD161, TCRγδ. To assess the presence of fibroblasts CD90 was targeted. The mean count of CD45+ hematopoietic cells in the tendinopathic samples was significantly higher than in the control samples, respectively 13.27% and 3.24% of the total cell count (P<0.001). The mean fraction of CD3+ cells present in the complete cell population was significantly higher in pathological samples than in control samples, respectively 1.70% and 0.37% (P<0.05). Presence of CD19+ B cells was not reported. The mean fraction of γδ T cells was significantly higher in tendinopathic samples compared to blood samples of the same patient and consisted of 12.9% and 5.8% γδ T cells respectively (P<0.05). These findings support an inflammatory cell infiltration in midportion Achilles tendinopathy that show similarities to enthesitis in SpA. This implies a potential target to investigate in novel treatment modalities

Objectives. To conduct a pilot randomised controlled trial to evaluate the feasibility of conducting a larger trial to evaluate the difference in Victorian Institute of Sports Assessment-Achilles (VISA-A) scores at six months between patients with Achilles tendinopathy treated with a platelet-rich plasma (PRP) injection compared with an eccentric loading programme. Methods. Two groups of patients with mid-substance Achilles tendinopathy were randomised to receive a PRP injection or an eccentric loading programme. A total of 20 patients were randomised, with a mean age of 49 years (35 to 66). All outcome measures were recorded at baseline, six weeks, three months and six months. Results. The mean VISA-A score for the injection group at the primary endpoint of six months was 76.0 (95% confidence interval (CI) 58.3 to 93.7) and for the exercise group was 57.4 (95% CI 38.1 to 76.7). There was no statistically significant difference between these scores (p = 0.171), which was expected from such a pilot study. Conclusions. This pilot study has been key to providing data to inform a larger study and shows that the methodology is feasible. Cite this article: Bone Joint Res 2013;2:227–32

Objective: To report the outcome of surgery for chronic recalcitrant Achilles tendinopathy in sedentary and athletic subjects. Design: Case control study. Participants: We matched each of the 61 non-athletic patients with a diagnosis of tendinopathy of the Achilles tendon with an athletic patient with tendinopathy of the main body of the Achilles tendon of the same sex who was within two years of age at the time of operation. A match according was possible for 56 patients (23 males and 33 females). 48 sedentary subjects and 45 athletic subjects agreed to participate. Main Outcome Measure: Outcome of surgery, return to sport, complication rate. Results: Non-athletic patients were shorter and heavier than athletic patients. They had greater BMI, calf circumference, side-to-side calf circumference differences, and subcutaneous body fat than athletic patients. Of the 48 sedentary patients, only 25 reported an excellent or good result. Of these, three had undergone a further exploration of the Achilles tendon. The remaining patients could not return to their normal levels of activity. In all of them, pain significantly interfered with daily activities. Conclusions: Non-athletic subjects experience more prolonged recovery, more complications, and a greater risk of further surgery than athletic subjects with recalcitrant Achilles tendinopathy. Key words: Achilles tendinopathy, surgery

Eighty-one patients treated surgically for non-insertional Achilles’ tendinopathy between 1987 and 1999 by one surgeon were reviewed by a comprehensive postal questionnaire. Fifty-six patients (73 tendons) returned a questionnaire at an average of 58.7 months after surgery. The duration of preoperative symptoms averaged 24.6 months. In all cases, conservative treatment was first attempted but failed to alleviate symptoms. Twenty (35.7%) of these patients were involved in competitive or serious recreational sport. There were 34 men and 22 women with a mean age of 42.5 years (range: 23 to 66). All patients who had insertional tendinopathy or retrocalcaneal bursitis were excluded from this study. The surgical procedure consisted of excision of the paratenon circumferentially and early mobilisation. All patients had the same post operative treatment. There were 77.5% excellent, 6.4% good, 6.4% fair and 6.4% poor results. Eleven percent developed complications post operatively. We concluded that surgical decompression of the Achilles’ tendon is a very effective treatment for patients with non-insertional Achilles’ tendinopathy who have failed conservative treatment

Background:. Achilles pathology is a serious and frequently occurring problem, especially in elite athletes. Recent research has suggested a role for the plantaris tendon in non-insertional achilles tendinopathy. We report on the outcomes after excision of the plantaris tendon in elite athletes. Aim:. To assess whether or not excising the plantaris tendon improves the symptoms of Achilles tendinopathy in elite athletes. Methods:. A group of 32 elite athletes who underwent plantaris tendon excision to treat medially located pain associated with non-insertional Achilles tendinopathy were investigated. Outcomes were assessed with pre and post-operative Visual Analogue Scores (VAS) for pain and the Foot and Ankle Outcome Score (FAOS) as well as time to return to sport and satisfaction scores. Results:. At a mean follow-up of 22.4 months (12–48), 29/32 (90%) of athletes were satisfied with the results. 30/32 athletes (94%) returned to sport at a mean of 10.3 weeks (5–27). The mean VAS score improved from 5.8 to 0.8 (p<0.01) and the mean FAOS improved in all domains (p<0.01). Conclusions:. The plantaris tendon may be responsible for symptoms in some patients with non-insertional Achilles tendinopathy. Excision using a mini-incision technique carries a low risk of complications and may provide significant improvement in symptoms enabling an early return to elite level sports

Background Achilles tendinopathy is prevalent in athletes and individuals with an active lifestyle. It causes significant morbidity, which at times leads to changes in exercise habits. Recently, the VISA-A questionnaire, based on a visual analogue score to assess pain and activity, has been devised as a clinical tool to assess the severity of Achilles tendinopathy (minimum score – 0, maximum possible score – 100). Aim To assess the clinical progress in patients with Achilles tendinopathy using the VISA-A questionnaire. Method Thirty-four patients (18 males, mean age 44 years, range 23–67; 16 females, mean age 51 years, range 20–76) were selected to complete the VISA-A questionnaire, after a diagnosis of Achilles tendinopathy had been made at first and subsequent visits to a specialised outpatient clinic. Results The average pre-treatment VISA-A score was 39 (SD 22.8, range 3–82, 95% CI: 31–47). The patients received intensive physiotherapy, including graded progressive eccentric calf strengthening exercises, and were offered a peritendinous injection of Aprotonin and local anaesthetic if physiotherapy was ineffective. Surgery was performed in six patients when six months of conservative management failed to produce improvements. The average post-treatment VISA-A scores at the latest follow up was 50 (SD 26.5, range 1–97, 95% CI: 40.8–59.3), with a mean difference between pre and post-treatment scores of 11.5 (SD 18.8 range -28.5–67.5, 95% CI: 4.9–18). The mean VISA-A score in patients offered surgery was 36, and 20 in patients who received a peri-tendinous injection of Aprotonin and local anaesthetic. Conclusion The VISA-A score can identify patients who need more aggressive management, and can be used to monitor their progress

Background. Most patients with Achilles tendinopathy (AT) are treated successfully with physiotherapy ie eccentric calf training. In some patients gastrocnemius contracture persists. Three other publications have reported improvement in AT following gastrocnemius release, but this is the first series of patients to have proximal medial gastrocnemius release (PMGR) for AT. The purpose of this study was to review patients with refractory non-insertional and insertional AT treated by PMGR with a minimum followup of 18 months. Method. Sixteen PMGRs were performed over a two year period. Nine patients (10 PMGRs) were available for followup. The mean age of patients was 45 (Range, 25 to 63) years, with five female and four male subjects. The average followup period was 2.5 (range, 1.7 to 3.3) years. The sample was divided into non-insertional and insertional tendinopathy, with five PMGRs per group. Outcome measures were VAS scores, VISA-A scores, AOFAS ankle-hindfoot score and overall satisfaction. Complications and further procedures were also recorded. Results. At an average of 2.5 years follow-up, two-thirds of patients were highly satisfied. The non-insertional tendinopathy group enjoyed better results than the insertional group: mean improvement in VISA-A scores were 59% (non-insertional) vs 22% (insertional); mean AOFAS scores improved by 29% (non-insertional) vs 15% (insertional). The improvement in the non-insertional group was statistically significant (p < 0.05) in all three outcome measures. Our findings further support that insertional tendinopathy is more resistant to calf stretching/lengthening treatments. Conclusion. In contrast to open or percutaneous debridement of the Achilles tendon, PMGR is a day surgical procedure that is well tolerated with excellent wound healing. Patients with non-insertional tendinopathy who have failed conservative treatment can expect significant improvement with VISA-A scores normalising after the procedure. We recommend PMGR for patients suffering recalcitrant non-insertional AT in whom gastrocnemius contracture persists despite an eccentric stretching program

Excessive apoptosis has been found in torn supraspinatus tendon1 and mechanically loaded tendon cells2. Following oxidative and other forms of stress, one family of proteins that is often unregulated are Heat Shock Proteins (HSPs). The purpose of this study was to determine if HSPs were unregulated in human and rat models of tendinopathy and to determine if this was associated with increased expression of regulators of apoptosis (cFLIP, Caspases 3& 8). A running rat supraspinatus tendinopathy overuse model 3 was used with custom microarrays consisting of 5760 rat oligonucleotides in duplicate. Seventeen torn supraspinatus tendon and matched intact subscapularis tendon samples were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from ten patients undergoing arthroscopic stabilisation surgery and evaluated using semiquantative RT-PCR and immunohistochemistry. Rat Microarray: Upregulation of HSP 27 (×3.4) & 70 (×2.5) and cFLIP (×2.2) receptor was noted in degenerative rat supraspinatus tendon subjected to daily treadmill running for 14 days compared to tendons of animals subject to cage activity only. Histological analysis: All torn human supraspinatus tendons exhibited changes consistent with marked tendinopathy. Matched subscapularis tendon showed appearances of moderate-advanced degenerative change. Apoptosis mRNA expression: The expression levels of caspase 3 & 8 and HSPs 27 & 70 were significantly higher in the torn edges of supraspinatus when compared to matched subscapularis tendon and control tendon (p< 0.01). cFLIP showed significantly greater (p< 0.001) expression in matched subscapularis compared to supraspinatus and control tendon. Immunohistochemical analysis: cFLIP, Caspase 3 & 8 and HSP 27 and 70 was confirmed in all samples of torn supraspinatus tendon. Significantly increased immunoactivity of Caspase 3& 8 and HSP 27 & 70 were found in torn supraspinatus (p< 0.001) compared to matched and normal subscapularis. The proteins were localized to tendon cells. The finding of significantly increased levels of Heat Shock Proteins in human and rat models of tendinopathy with the co-expression of other regulators of apoptosis suggests that Heat Shock Proteins play a role in the cascade of stress activated-programmed cell death and degeneration in tendinopathy

Summary Statement. The peripheral neuronal phenotype is significantly altered in rotator cuff tendinopathy (RCT) with a clear upregulation of the Glutaminergic system being present in disease. Introduction. Shoulder pain is the third most frequent cause of chronic musculoskeletal pain in the community and is usually caused by rotator cuff tendinopathy (RCT). The central and peripheral nervous system play an important role in both tissue homoeostasis and tendon healing. The Glutaminergic system is of key importance in driving the peripheral and central neuronal changes which increase the body's sensitivity to pain (1, 2). No study to date has investigated the role of the glutaminergic system in human RCT. We hypothesised that the peripheral neuronal phenotype would be altered in RCT, and would vary according to disease stage as measured by size of tear. The term ‘peripheral neuronal phenotype’ is used to refer to refer to specific characteristics of the peripheral nervous system, neuronal mediators and the receptors for these mediators in peripheral tissue. Methods. Rotator cuff tendon specimens were obtained from 64 patients undergoing the surgical repair of rotator cuff tears. Control supraspinatus tendon was obtained from 10 patients undergoing surgery for anterior instability using an ultrasound guided biopsy technique. Patients with rotator cuff tears were divided into 2 groups: the small/medium group (≤ 3cm size) and the large/massive group (>3cm size). The tendon tissue was histologically stained using Haematoxylin and Eosin, and immunohistochemically stained with primary antibodies visualised using 3, 3′-diaminobenzidine (DAB). Image analysis was performed blindly by 2 observers using Image-J to quantify the amount of DAB positive staining. Data was non-parametric in distribution and Mann-Whitney U tests were carried out using SPSS with significance levels set at a minimum of p<0.025. Results. There were significant changes in the peripheral neuronal phenotype in RCT. The Glutaminergic system was significantly up-regulated with an increase in Glutamate and changes in several related receptors in disease versus control (p<0.01). The standard deviation in nuclei count and mean cell nuclear area were both increased in disease (p<0.01) compared to controls. Tendon vascularity and cell proliferation were reduced in disease vs control (p<0.01). There were no significant correlations between pain scores and the peripheral tissue markers. Discussion/Conclusion. The peripheral neuronal phenotype is significantly altered in rotator cuff tendinopathy (RCT) with clear changes in the Glutaminergic system in disease. These findings are novel and improve our understanding of pain and tissue healing in RCT, potentially providing novel therapeutic targets

Introduction. Achilles tendinopathy (AT) is a highly prevalent injury in athletes and non-athletes with an unknown aetiology. Genetic risk factors have been a recent focus of investigation. The aim of this systematic review was to determine which loci have been linked with mid-portion AT and could potentially be used as biomarkers in tendinopathy risk models or as preventative or therapeutic targets. Materials and Methods. Eight electronic bibliographic databases were searched from inception to April 2015 for cross-sectional, prospective cohort and case-control studies that included empirical research investigating genes associated with mid-portion AT. Potential publications were assessed by two independent reviewers (AAC and PRJ) for inclusion and quality. Quality was evaluated using a validated scale. Results. Twelve candidate gene studies and three pathway-based genetic association studies that investigated genetic risk factors for AT were identified. According to Ariëns's criteria, there was strong evidence for the COL5A1 gene. There was some evidence for 6 of the other genes investigated: COL5A3, TNC, CASP8, MIR608, GDF5, MMP3 and TIMP2 genes. There was inconclusive evidence for the following genes: COL3A1, COL5A2, COL11A1, COL11A2, COL12A1, COL1A1, COL27A1, COL14A1, COMP, THBS2, ADAMTS2, ADAMTS5, ADAMTS14, ADAM12, TGFβ1, IL-1β, IL-1RN, IL-6, NOS2 and NOS3. There was some evidence for combinations of functional variants of different genes and pseudohaplotypes constructed from many functional variants. The quality of included studies varied (3/9 to 7/9), and the average quality assessment score was 5.5/9 (61%). Discussion. There are genetic differences between subjects with and without AT. To further elucidate these findings, prospective studies are needed to investigate the increased risk associated with specific genetic findings. Modifying training loads or preventative exercise may be used to mitigate increased risk, although it needs to be highlighted that a genetic association does not necessarily mean an individual will develop Achilles tendinopathy. Gene therapy may have a role in tendon healing, but further research is necessary to develop risk models and establish the most advantageous genes to transfer

Aim. To determine the effect of the use of radial extracorporeal shockwave therapy (rESWT) in the treatment of patellar tendinopathy. Methods. Between 2005 and 2010, twenty eight patients (34 knees), who showed poor or no result from conservative management, had rESWT for patellar tendinopathy. The device used is Swiss Dolorclast¯(EMS, Switzerland). All patients received three weekly sessions of 2000 impulses at 3.0 bar (energy flux density = 0.14 mJ/mm. 2. ) and a frequency of 15 Hz. We assessed pain, function and activity and quality of life of the patient before and three months after treatment using KOOS (Knee Injury and Osteoarthritis Outcome Score). Results. There were 21 males (25 knees) and 7 females (9 knees) with a median age of 31 years (18 - 60). Twenty two of the 28 patients (78.6%) reported excellent or good improvement. After three months of treatment with rESWT, the average KOOS score increased from 50.4 to 71.1 (p = 0.004). Conclusion. This study has shown that radial extracorporeal shockwave therapy demonstrated an improvement in the functional activity and reduction in the pain. Patellar tendinopathy that does not respond to conservative management can be successfully treated with rESWT

Aim: The purpose of this study was to evaluate the cytokine molecules present in a rat tendinopathy model and in the torn edge of human rotator cuff tendon in an attempt to understand their role in tendon degeneration. Methods: A rat tendon overuse model was used with custom microarrays consisting of 5760 rat oligonucleotide features in duplicate. Seventeen torn supraspinatus tendon and matched intact subscapularis tendon samples were collected from patients undergoing arthroscopic shoulder surgery.Control samples of subscapularis tendon were collected from ten patients undergoing arthroscopic stabilisation surgery.Specimens were analysed for the presence of interleukins 18, 15, 12, 11, 6, 2, macrophage inhibitory factor (MIF), and tumour necrosis factor ƒÑ by semiquantitative RT-PCR and immunohistochemistry. Tendinopathy was assessed on a basic histological scale. Results: Rat Microarray analysis: Upregulation of IL-6, IL-11 and IL18 receptor was noted in the degenerated rat supraspinatus tendon. Downregulation of IL-2 was noted. No other cytokine signal was expressed. Histological analysis: All torn human supraspinatus tendons changes consistent with marked tendinopathy. Matched subscapularis tendon showed appearances of moderate-advanced degenerative change. Cytokine mRNA expression: TNF-£\ mRNA expression was found to be significantly elevated (p< 0.01) in subscapularis tendon compared to torn supraspinatus samples. The expression levels of IL-18, IL-15, IL-6 and MIF was significantly higher in the torn edges of supraspinatus when compared to matched subscapularis tendon and normal control tendon (p< 0.001). Immunohistochemical analysis: Presence of IL-18, IL-15, Il-6, MIF and TNF-£\ was confirmed in all samples of torn supraspinatus tendon. Significantly increased levels of IL-18, IL-15, IL-6 and MIF were found in torn supraspinatus. (p< 0.01) compared to matched and normal subscapularis. Conclusions: Cytokines have been shown to promote the intensive production of reactive O2 metabolites . 1. and are potent agonists of protein kinases . 2. Our finding of significantly increased cytokine levels may suggest that these molecules when expressed during the degenerate and healing phases of tendon injury result in the subsequent production of reactive O2 species and protein kinases. 3. causing tendon damage or failure of the normal reparative process. Our finding of marked tendinopathy in matched subscapularis tendon may also provide a useful human tendinopathy model

Achilles tendinopathy is characterised by chronic degeneration of the Achilles tendon, usually secondary to injury or overuse. Extracorporeal shockwave treatment (ESWT) is of potential benefit in refractory cases where conservative management with analgesia, physiotherapy and corticosteroid injection have been unsuccessful. Patients with refractory Achilles tendinopathy enrolled between October 2010 and October 2011 received three sessions of ESWT over three weeks. Patients completed visual analogue scale (VAS) scores for pain at rest and on activity and the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire pre-treatment. These outcome measures and a six-point Likert satisfaction scale were reassessed at six and 16 weeks post treatment. 51 patients completed follow up. Mean age was 56 (34–80) years and mean length of symptoms 34 (4–252) months. Significant improvement (p<0.05) in VAS scores (rest and activity) and VISA-A scores was observed between baseline and 16 weeks. Mean Likert score was 3 (somewhat improved) at 16 weeks. Patients suffering Achilles tendinopathy for longer than 25 months had significantly less improvement than those affected for a shorter period. This study suggests that ESWT improves subjective and objective outcomes in patients with refractory Achilles tendinopathy

Achilles tendinopathy is chronic degeneration of the Achilles tendon, usually secondary to injury or overuse. It involves a triad of pain, swelling and impaired function. Primary treatment is rest, analgesia, corticosteroid injections and physiotherapy (eccentric training and heel pads to correct gait). Some patients remain symptomatic and further treatment options need considering. NICE produced a document from the Interventional Procedures Advisory Committee in 2009 which reviewed the literature and evidence for extracorporeal shockwave treatment (ESWT). Low energy shock wave treatment (SWT) is thought to stimulate soft tissue healing, inhibit pain receptors and promote angiogenesis. NICE guidance was that ESWT could be used in refractory Achilles tendinopathy if used for clinical governance, audit or research. Patients with refractory Achilles tendinopathy were enrolled between October 2010 and 2011. They received three sessions of ESWT over three week. Patients completed visual analogue scale (VAS) scores for pain at rest and on activity and the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire pre-treatment. These outcome measures and a six-point Likert satisfaction scale (six points, high is worsening) were reassessed at 6 and 16 weeks post treatment. 51 patients completed follow up. The mean age was 56 (34–80) years and mean length of symptoms 34 (4–252) months. There was a significant improvement (p<0.05) in VAS scores observed from baseline and 16 weeks post treatment. This was also the case in the VISA-A scores. The mean Likert score was 3 (somewhat improved) at 16 weeks but there was no statistical significance. This study suggests that ESWT improves subjective and objective outcomes in patients with refractory Achilles tendinopathy. Patients over 60 possibly have a worse outcome along with patient who had symptoms for over 25 months. Follow up scores at one year are due to be collected and the data will be submitted to NICE

Introduction. The COL5A1 gene encodes for the α1 chain of type V collagen, a minor fibrillar collagen that is an important regulator of collagen fibrillogenesis. Several polymorphisms, including rs12722 (C/T), within the 3′-UTR of COL5A1 are associated with chronic Achilles tendinopathy and other musculoskeletal soft tissue injuries as well as exercise-related phenotypes. It is hypothesised that polymorphisms within the 3′-UTR regulate the amount of the α1(V) chain synthesised and type V collagen production. This in turn influencing the mechanical properties of tendons and other musculoskeletal soft tissues. In our laboratories, two major functional forms, namely the T- and C-allelic forms of the COL5A1 3′-UTR, were identified and associated predominately with severe chronic Achilles tendinopathy and healthy asymptomatic control individuals, respectively. Materials and Methods. To further investigate the functional differences between the two major 3′-UTR functional forms as well as to start mapping the regions which are responsible for the tendinopathic phenotype, skin biopsies from donors having a known genotype at rs12722 and primary fibroblast cell lines were established in order to quantify COL5A1 and COL1A1 expression levels in a pilot study. Lastly, in preliminary RNA EMSAs, biotinylated C- and T-allelic RNA probes for a specific 57bp functional region within the 3′-UTR were incubated with either fibroblast nuclear or cytoplasmic protein extracts to investigate putative distinguishing RNA:RBP complex formation. Results. An overall higher relative mRNA expression of both COL5A1 (p<0.001) and COL1A1 (p=0.0015) were observed in primary skin fibroblasts from donors having a rs12722 TT genotype compared to donors with a CC genotype. A unique RNA:RBP complex was also identified with the C-allelic probe. Discussion. These novel results have important implications for our understanding of the proposed role of type V collagen in the aetiology of tendon and other musculoskeletal soft tissue injuries, as well as, other exercise-related phenotypes

Summary Statement. ASTM therapy is commonly used to treat Achilles tendinopaty. However, there was no report to evaluate the biomechanical effects, especially the dynamic viscoelasticity. We have shown that ASTM treatment was biomechanically useful for chronic Achilles tendinopathy in an animal model. Introduction. Achilles tendinopathy is a common chronic overuse injury. Because Achilles tendon overuse injury takes place in sports and there has been a general increase in the popularity of sports activities, the number and incidence of Achilles tendon overuse injury has increased. Augmented Soft Tissue Mobilization (ASTM) therapy is a modification of traditional soft tissue mobilization and has been used to treat a variety of musculoskeletal disorders. ASTM therapy is thought to promote collagen fiber realignment and hasten tendon repair. It might also change the biomechanical behavior of the injured tendon, especially the dynamic viscoelasticity. The purpose of this study is to evaluate the effect of ASTM therapy in a rabbit model of Achilles tendinopathy by quantifying dynamic biomechanical properties and histologic features. Patients & Methods. The hind limbs of 12 rabbits were used, and 24 Achilles tendons were injected with collagenase to produce tendon injury. One hind limb of each animal was then randomly allocated to receive ASTM therapy, while the other received no treatment and served as a control. ASTM was performed on the Achilles tendon for 3 minutes on postoperative days 21, 24, 28, 31, 35, and 38. The Achilles tendons were harvested 10 days after the last treatment. Specimens were examined with dynamic viscoelasticity and light microscopy. Results. The mean±SD cross-sectional area for the treated and untreated tendons was 12.30±5.47 mm. 2. and 9.57±8.36 mm. 2. , respectively. The difference between the treated and untreated tendons was statistically significant (P<.01). At all dynamic loading frequencies, the storage modulus in the untreated tendons tended to be higher than that in the treated tendons. At 0.1 Hz and 10 Hz, in the untreated tendons was significantly higher than that in the treated tendons (P=.05). The loss modulus was significantly lower in the treated tendons than in the untreated tendons (P<.05). There was no significant difference in tan δ between the treated and untreated tendons. HE stain showed that the untreated tendon fiber was wavy and kinking and displayed a disordered collagen arrangement. In contrast, the tendon fiber was well aligned in the treated tendons. In the immunohistochemically stained specimens, the type III collagen showed higher color intensity in the untreated tendons than in the treated tendons. Discussion/Conclusion. We have shown that ASTM was a biomechanically useful treatment for chronic Achilles tendinopathy. Biomechanical and histologic data showed the treated Achilles tendons had better biomechanical function and histologic outcomes than the untreated tendons

The aim of this study was to investigate the occurrence of tissue hypoxia and apoptosis at different stages of tendinopathy and tears of the rotator cuff. We studied tissue from 24 patients with eight graded stages of either impingement (mild, moderate and severe) or tears of the rotator cuff (partial, small, medium, large and massive) and three controls. Biopsies were analysed using three immunohistochemical techniques, namely antibodies against HIF-1α (a transcription factor produced in a hypoxic environment), BNip3 (a HIF-1α regulated pro-apoptotic protein) and TUNEL (detecting DNA fragmentation in apoptosis). The HIF-1α expression was greatest in mild impingement and in partial, small, medium and large tears. BNip3 expression increased significantly in partial, small, medium and large tears but was reduced in massive tears. Apoptosis was increased in small, medium, large and massive tears but not in partial tears. These findings reveal evidence of hypoxic damage throughout the spectrum of pathology of the rotator cuff which may contribute to loss of cells by apoptosis. This provides a novel insight into the causes of degeneration of the rotator cuff and highlights possible options for treatment

Introduction. The exact mechanisms leading to tendinopathies and tendon ruptures remain poorly understood while their occurrence is clearly associated with exercise. Overloading is thought to be a major factor contributing to the development of tendon pathologies. However, as animal studies have shown, heavy loading alone won't cause tendinopathies. It has been speculated, that malfunctioning adaptation or healing processes might be involved, triggering tendon tissue degeneration. By analysing the expression of the entirety of degrading enzymes (degradome) in pathological and non-pathological, strained and non-strained tendon tissue, the aim of this study was to identify common or opposite patterns in gene regulation. This approach may generate new targets for future studies. Materials and Methods. RNA was extracted from different tendon tissues: normal (n=7), tendinopathic (n=4) and ruptured (n=4) Achilles tendon; normal (n=4) and tendinopathic (n=4) posterior tibialis tendon; normal hamstrings tendon with or without subjection to static strain (n=4). The RNA was reverse transcribed, then pooled per group The expression of 538 protease genes was analysed using Taqman low-density array quantitative RT-PCR. To be considered relevant, changes had to be at least 4fold and measurable at a level below 36 Cts. Results. In general, there was little common regulation when exercised was compared with pathological tissue. The expression of PAMR1 and TNFαIP3 was upregulated with exercise (169-fold and 78-fold), Achilles tendinopathy (9724-fold and 7-fold) and Achilles tendon rupture (1809-fold and 10-fold), while DDI1, PSMB11 and PSH2 which were down-regulated with exercise were upregulated with Achilles pathology. Discussion. The newly found targets may deliver insights into the initiation and progression of tendon pathologies: PAMR1, a regeneration associated muscle protease which has been shown to be downregulated in Duchenne muscular dystrophy and upregulated in regenerating muscle fibers, might also be involved in tendon regeneration; TNFαIP3, which negatively regulates the NF-κB/pro-inflammatory pathway, could have anti-inflammatory function in tendon regeneration. PSMB11 and PSH2 are for the first time shown to be expressed in tendon and regulated in tendon pathology. Using this approach we were able to generate new targets and to add information on function, regulation and expression sites of recently identified proteins

Introduction. Chronic Achilles tendinopathy is a common overuse injury. There are several modalities of treatment, reflecting difficulties in its management. In particular, due to the well-recognised morbidity associated with surgical decompression, treatment has steered towards a less invasive route. Dry needling has been efficacious in managing other tendinopathies. This study therefore assessed dry needling and percutaneous hydrostatic decompression of the Achilles tendon as a novel treatment for this condition. Methods. Twenty-two patients with 27 sonographically-confirmed chronic Achilles tendinopathy were prospectively enrolled. All were symptomatic for >6 months and have failed alternative conservative treatments. Ultrasound-guided dry needling of neovascular areas and paratenon hydrostatic decompression was performed by a dedicated musculoskeletal radiologist on a 6-weekly basis until symptomatic resolution or no improvement was evident. Sonographic assessment of the tendon's thickness and neovascularity was undertaken. Following treatment, a standardized physiotherapy regime was adopted. At baseline and 6 weeks post-final procedure, visual analogue scores (VAS) at rest and during activity were obtained. Telephonic interviews were carried out 12 and 24 months post-treatment. Results. 24 tendons (in 19 patients) were successfully treated - 1 patient had spontaneous symptomatic resolution and 2 progressed to surgical intervention. The mean number of treatment sessions was 2. There was no significant change in neovascularity or tendon thickness after treatment. Therapeutic intervention led to a significant improvement in VAS at rest (42 v 18.4, p=0.0005) and during activity (74 v 33.7, p< 0.0001). At 12 months, 77% of patients were >80% satisfied with their outcome of the procedure, with 85% of patients able to return to their sporting interests. At 24 months, 90% of patients were >80% satisfied with their outcome, with nearly half having complete symptomatic resolution. Conclusion. Dry needling and percutaneous paratenon decompression under ultrasound guidance shows promise as an alternative treatment for this chronic condition

The objective was to seek evidence of hypoxia in early human tendinopathy and thereafter, to explore mechanisms whereby tissue hypoxia may regulate apoptosis, inflammatory mediators and matrix regulation in human tenocytes. Fifteen torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from 10 patients undergoing arthroscopic stabilisation surgery. Markers of hypoxia were quantified by immunohistochemical methods. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon ACL reconstruction. The impact of hypoxia upon tenocyte biology ex vivo was measured using quantitative RT-PCR, multiplex cytokine assays, apoptotic proteomic profiling, immunohistochemistry and annexin V FACS staining. Increased expression of HIF 1a, Bcl-2 and clusterin (hypoxic and apoptotic markers) was detected in subscapularis tendon samples compared to both matched torn samples and non matched control samples (p<0.01). Hypoxic tenocytes exhibited increased production of proinflammatory cytokines (p<0.001), altered matrix regulation (p<0.01) with increased production of Collagen type III operating through a MAPK dependent pathway. Finally, hypoxia increased expression of several mediators of apoptosis and thereby promoted tenocyte apoptosis. Hypoxia promotes expression of proinflammatory cytokines, key apoptotic mediators and drives matrix component synthesis towards a collagen type III profile by human tenocytes. We propose hypoxic cell injury as a critical pathophysiological mechanism in early tendinopathy offering novel therapeutic opportunities in the management of tendon disorders

Introduction: The results of treatment of Achilles tendinopathy are described in the sporting community little is known of the long-term results in the general population. Our aim was to assess these results in a district general hospital setting. Materials/Methods: Patients who had undergone treatment for Achilles tendinopathy were identified from hospital records and assessed by postal questionnaire. This consisted of two parts (the VISA-A and a section about occupation, duration of symptoms prior to referral, prior sporting activities, and satisfaction). This was sent out with a stamped addressed return envelope, in the case of non-reply this was followed by a second one, and finally the patient was contacted by phone. Clinical notes of responders were reviewed. Results: 71 patients were identified and the response rate was 83% with an equal, male to female split. Average age was 45; mean time to follow up was 8 years. Patients had undergone a wide variety of treatments (73% physiotherapy, 45% heel raises, 24% steroid injection {there were no ruptures reported}, and 12% operative). Duration of symptoms prior to referral ranged from 2 weeks to 27yrs. 78% were very satisfied or satisfied. 46% undertook sport prior to onset of symptoms, and at the time of follow up 40% undertook sport. 81% did not change their occupation. Average VISA-A score was 50 (range 10–90). Discussion: Despite an average VISA-A score of 50 (excellent 90–100, good 75–85, fair 60–70, poor< 50), after a follow period up of 8 years, most patients were satisfied with the treatment they had received. We could find no correlation between treatment and eventual outcome. Conclusion: Patients generally have continued symptoms from their Achilles Tendinopathy, many years later, despite standard treatments, which is reflected in poor VISA-A scores

Summary. Treatment of equine naturally occurring over-strain tendinopathy with mesenchymal stem cells suspended in bone marrow supernatant resulted in significant improvements compared to saline treated tendons in the normalisation of biomechanical, morphological, and compositional parameters with no adverse effects. Introduction. Tendon injuries are a common age-related degenerative condition where natural repair involves scarification, resulting in a functionally inferior tissue. 1. that frequently re-injures. Naturally-occurring human and equine tendinopathy possess many similarities. 2. making the horse a good clinically-relevant model. A multitude of treatments are used but few have a strong evidence base. Regenerative approaches using mesenchymal stem cells (MSCs) to improve outcome are supported by clinical data demonstrating reduced re-injury rates in racehorses. 3. We therefore hypothesised that implantation of autologous MSCs into injured equine tendons would result in a tissue more closely resembling normal tendon matrix than the fibrous scar tissue formed subsequent to natural repair. The aim of this controlled experimental study was to assess the biomechanical, histological and compositional parameters following MSCs implantation into naturally injured tendons. Methods. This study was carried out following informed consent from the owners of donated horses and under Institutional Ethics and Welfare Committee approval and UK Home Office Licences. Thoroughbred and Thoroughbred cross horses aged between 5 and 15 (mean 7.8±3.0) years, suffering career-ending severe superficial digital flexor tendinopathy (SDFT) within the metacarpal region of the forelimb of less than 2 months duration (average 30 days) were recruited. Autologous bone marrow derived MSCs were expanded and 1×10. 7. MSCs in 2ml of citrated bone marrow supernatant were injected into the central defect of the damaged SDFT as described. 2. in 6 horses. The control group (6 horses) received an identical volume of isotonic saline. The horses then entered a standardised ascending exercise rehabilitation regimen of walking (3 months) and walking combined with trotting (next 3 months) after which horses were euthanised. Treated and contralateral SDFTs were recovered and analysed for mechanical, histological (blinded), and compositional parameters. Results. The treated tendons exhibited statistically significant improvements in all parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, in comparison to saline-treated tendons, MSC treated tendons had significantly improved elasticity (p<0.05), lower (improved) histological scoring of organisation (p<0.001) and crimp pattern (p<0.05), lower cellularity from histological scoring (p<0.002) and DNA content (p<0.05), reduced vascularity (p<0.03), water content (p<0.05), GAG content (p<0.05). Total collagen content was unaltered between groups and interestingly, while tissue-linked fluorescence (indicator of collagen age) was similar between treatment and control groups, both were significantly lower than the contralateral limb (p<0.014), which suggested similar amounts of new collagen in the injured limbs. A higher remodelling rate, exemplified by increased MMP-13 activity, was also demonstrated for the control group compared to the MSC treated group and contralateral limbs (p<0.02). Conclusion. This data support the hypothesis that the injection of MSC with BM supernatant results in a tissue more like normal tendon matrix rather than the fibrous scar tissue formed after natural injury and repair. The mechanism of this effect is not clear but the improved tissue elasticity, reduced vascularity, cell content and GAGs is more consistent with an immunomodulatory role for MSCs with a subsequent reduction in fibrosis than a true regenerative effect

Aims: 1 To assess the histological changes in patients with Achilles tendinopathy. 2 To map the distribution of nerves and nerve endings within the Achilles tendon. Methods: Tendon biopsy specimens were taken from patients with spontaneous (ie previously painless) Achilles rupture patients and chronic painful tendinopathy patients. ‘Normal’ cadaveric /lacerated tendon biopsies were used for comparison. Sections were stained with H& E for basic histology. Immunolocalisation of nerve tissue was performed with 2 anti-neurofilament antibodies. Non-specific immunoglobulin was used as a negative control. Results: The number of nerves and nerve endings found within the normal tendons and both groups of degenerate tendons was very low. Only 30% of the normal tendon sections showed any positive staining at all. Compared to 36% of ruptured tendon and 43% of the painful tendinopathy sections. Conclusions: Tendon rupture and chronic painful tendinopathy biopsies ALL show widespread degenerative changes. There is a paucity of nerve tissue within these tendons, which may have implications for the neurogenic hypothesis of tendon degeneration. There appear be more nerve fibres in vascular areas of the painful tendinopathy biopsies. There may be more nerve fibres in the peritendinous tissue

This is a prospective analysis on 30 physically active individuals with a mean age of 48.9 years (35 to 64) with chronic insertional tendinopathy of the tendo Achillis. Using a transverse incision, the tendon was debrided and an osteotomy of the posterosuperior corner of the calcaneus was performed in all patients. At a minimum post-operative follow-up of three years, the Victorian Institute of Sports Assessment scale – Achilles tendon scores were significantly improved compared to the baseline status. In two patients a superficial infection of the wound developed which resolved on antibiotics. There were no other wound complications, no nerve related complications, and no secondary avulsions of the tendo Achillis. In all, 26 patients had returned to their pre-injury level of activity and the remaining four modified their sporting activity. At the last appointment, the mean pain threshold and the mean post-operative tenderness were also significantly improved from the baseline (p < 0.001). In patients with insertional tendo Achillis a transverse incision allows a wide exposure and adequate debridement of the tendo Achillis insertion, less soft-tissue injury from aggressive retraction and a safe osteotomy of the posterosuperior corner of the calcaneum

Purpose: We evaluated the respective roles of acromioplasty and curettage of calcifications in arthroscopic treatment of calcifying tendinopathy of the rotator cuff. Material and methods: We reviewed 41 cases of calcifying tendinopathy at mean 42 months. We retained for analysis only true calcifications identified at least 12 months after arthroscopy. All patients underwent acromioplasty and 13 underwent calcification curettage. The physical examination searched for subacromial impingement and cuff tendon suffering. The weighted Constant score was determined to assess outcome as excellent, good, fair, or poor. Patient satisfaction was assessed using three subjective questions. We searched for persistent calcification on the AP and Lamy lateral x-rays and quantified acromial resection by measuring the height of the subacromial space, the acromial arrow, and the type of acromion (Bigliani). Ultrasonography was performed to search for cuff lesions. Cuffs were classed as normal, atrophic or torn. Results: After statistical analysis, the mean Constant score was found to have increased from 55 points to 80 points, with 88% excellent and good results (weighted Constant score > 85%). There was no significant difference between patients with and without calcification curettage (p> 0.1). Patients who were mobilised rapidly had a better outcome (p< 0.005). Subjectively, 88% of the patients were satisfied or very satisfied.These results were not correlated with duration of follow-up. The degree of preoperative calcification did not affect outcome, but persistent calcification (nine cases) had an unfavourable effect on outcome. Nevertheless, 80% of the calcifications without curettage did not resorb after acromioplasty. The type of acromion had an effect on outcome. Acromions which were not flat (type II or III) had an unfavourable influence. The degree of acromial correction had a significant effect on outcome, the Constant score increased proportionally with the height of the subacromial space and inversely with acromial arrow. Ultrasonography disclosed two cuff tears but in elderly subjects, probably due to degeneration. Conclusion: Curettage of calcifications does not improve outcome of good quality acromioplasty. The stage of the calcification is not an indication for curettage. Furthermore, it appears that the impingement is partly the cause of persistent calcifications since 80% of them disappeared after acromioplasty alone

Introduction and Objectives: patellar tendinopaty (or jumper’s knee) is a frequent problem that affects active young adults. In some cases the different conservative treatment options are innefective and surgical treatment is considered. The purpouse of this study is to determine if repeated intratendinous inyections of platelet rich plasma (PRP) are effective for the treatment of these refractary cases. Materials and Methods: Eight consecutive patients (4 males and 4 females, mean age 24+/−5,9) who presented refractary patellar tendinopathies were included. All patients had presented symptoms for at least 6 months and had recieved treatmet for at least 3 months. All patients had been subjected to activity limitation, physical therapy, NSAID’s and laser and ultrasound therapy. In 3 cases corticosteroid inyections had been used. The subjects were assesed before treatment and 3 months and one year later with a Visual Analoge pain Scale (0 to 100mm, VAS), the Victorian Institute of Sport Assessment Patellar tendinopathy assesment scale(VISA-P) and the Lysholm score. Treatment consisted of 3 infiltrations (one week apart) of 3 cm3 of PRP extracted from their own blood with the GPS. ®. system (Biomet, Warsaw, Indiana, U.S.A). The PRP was infiltrated at the level of the tender tendon and inmediately behind the tendon at the proximal tendinous insertion and 1 cm distal to it through a single cutaneous puncture. Results: Of the 8 patients, 7 presented a significant increase (more than 20 points) in the VISA-P score and 1 did not present any noticeable improvement. No complications related to the injections were observed. The VISA-P score increased from a pretreatment mean of 29 +/− 10.7 to 79 +/− 10.7 at one year (significant differences, p< 0.001). A similar decrease was observed in the VAS pain score (pretreatment values of 75+/−28 to one year values of 21+/−19). There were not significat differences in the Lysholm score. Conclusions: PRP seems to be a possible alternative to surgical treatment in refractary patellar tendinopathy

To evaluate the effects of eccentric strengthening exercises (ESE) in athletic patients with Achilles tendinopathy. Forty five athletic patients (29 men, average age 26 years; 16 women, average age 28 years; average height: 173 ± 16.8, range 158 to 191; average weight 70.8 kg ± 15.3, range 51.4 to 100.5) with clinical diagnosis of unilateral tendinopathy of the main body of the Achilles tendon completed the VISA-A questionnaire at first attendance and at their subsequent visits. The patients underwent a graded progressive eccentric calf strengthening exercises programme for 12 weeks. The mean pre-management VISA-A scores of 36 (SD 23.8; 95% C.I.: 29 – 46) improved to 52 (SD 27.5; 95% C.I.: 41.3 – 59.8) at the latest follow up (p = 0.001). Twenty seven of the 45 patients responded to the eccentric exercises. Of the 18 patients who did not improve with eccentric exercises, 5 (mean age: 33 years) improved with two peritendinous aprotinin and local anaesthetic injections. 10 of the 18 patients (9 men, mean age 35 years; 1 woman aged 40 years) who did not improve with eccentric exercises and aprotinin injections proceeded to have surgery. The remaining three patients (3 women, mean age 59.6 years; 2 men, mean age 63 years) of the 18 non-responders to eccentric exercises and aprotinin injections declined surgical intervention. ESE in athletic patients provide comparable clinical outcome compared to our previous results in non-athletic patients. ESE are a viable option for the management of AT in athletes, but, in our hands, only around 60% of our athletic patients benefited from an intensive, heavy load eccentric heel drop exercise regimen alone. If ESE fail to improve the symptoms, aprotinin and local anaesthetic injections should be considered. Surgery is indicated in recalcitrant cases after 3 to 6 months of non operative management

Introduction. Chronic mid body Achilles tendinopathy is a common problem. There is no consensus on treatment. The aim of this review was to assess the effectiveness of physiotherapy interventions (non surgical and non pharmacological) for this condition. Methods. A systematic review of the literature was conducted. A search of published and grey literature databases was undertaken (1999- December 2010). Two reviewers independently assessed the studies for eligibility using a strict inclusion and exclusion criteria. All eligible articles were assessed critically using the Pedro score. Data on cohort characteristics, diagnostic criteria, treatment intervention, outcome measures and results was extracted. A narrative research synthesis method was adopted. Results. 209 studies were identified. Nine publications met the review inclusion criteria. Methodological quality was adequate for all nine studies; however, blinding was a limitation for most. Interventions investigated were; Exercises (n = 2), Low level laser therapy (n = 1), Low energy shockwave treatment (SWT) (n = 3), Air cast brace (n = 2) and Insoles (n = 1). Some evidence exists for eccentric exercises in combination with SWT or Laser. However, contrary to other reviews, eccentric exercises were not found to be superior to other physiotherapy treatments. Conclusions. There is insufficient evidence to determine which method of physiotherapy is most appropriate for a chronic Achilles tendinopathy. Further well designed randomised controlled trials assessing physiotherapy interventions with specific diagnostic criteria and appropriate outcome tools are required to determine the efficacy of physiotherapy for the condition

Introduction. The mainstay of treatment in non-insertional Achilles tendinopathy is non-operative, however between 1/4 and 1/3 of patients fail this. The main symptom is pain which appears to be related to new nerve endings that grow into the tendon with the neovessels from the paratenon. Treatments which strip the paratenon from the tendon are showing promise including formal paratenon stripping via Achilles tendinoscopy. The pain and swelling in Achilles tendinopathy is usually on the medial side leading to the postulation that the plantaris tendon may have a role to play. Methods. We report a consecutive series of 11 patients who underwent Achilles tendinoscopy with stripping of the paratenon and division of the plantaris tendon, above the level of the tendinopathic changes in the Achilles. All patients had failed conservative treatment for at least 6 months and requested surgical intervention. The patients were scored with the SF-36, AOS and AOFAS hindfoot questionnaires pre-operatively and at a minimum of 2 years post operatively. They also recorded their level of satisfaction with the treatment at final follow up. Results. The mean AOFAS scores significantly improved from 68 pre-op to 92 post op (p = 0.0002) as did the AOS scores for both pain (28% pre-op to 8% post op (p=0.0004)) and disability (38% pre-op to 10% post op (p=0.0005). The mean SF-36 scores also improved but were not statistically significant (pre-op 76 post op 87 (P = 0.059). There were no complications. 8 of the 11 patients were satisfied, the other 3 somewhat satisfied. Conclusion. The results of Achilles tendinoscopy and division of the plantaris tendon are encouraging but further studies are required to compare it to other treatments. It is minimally invasive and low risk so should not affect the ability to perform a formal open procedure if unsuccessful

Purpose: Arthroscopic treatment of calcified tendinopathy is classically performed in two times: exploration of the glenohumeral joint followed by subacromial arthroscopy to evacuate the calcification. In our experience, glenohumeral arthroscopy has only exceptionally provided a diagnostic element. In addition, the principal complication of this procedure is retractile capsulitis which may be a secondary effect of glenohumeral aggression. We conducted a retrospective analysis to assess the effect of systematic exploration of the glenohumeral joint. Material and methods: Two homogeneous groups of patients were identified. Group 1 included 32 patients who had had glenohumeral arthroscopy then resection of the calcifications using a bursoscope. Group 2 included 32 patients whose treatment was limited to subacromial arthroscopy for resection. The preoperative Constant score (52 in group 1 and 54 in group 2), disease duration (34 and 40 months respectively), and localisation of the calcification were comparable for the two groups. Acromioplasty was not performed in these patients. All were reviewed at minimal follow-up of 6 months for assessment of the Constant score and a radiography study. Results: At last follow-up the mean Constant score was 70 in group 1; calcifications had disappeared in 84% of the cases and delay to recovery (total pain relief and return to work) was 11 months. There were 4 cases of postoperative capsulitis (12.5%). The mean Constant score was 79 in group 2; calcifications had disappeared in 78% of the cases and delay to recovery was 6.5 weeks (p = 0.0001). There was one case of retractile capsulitis (3%). In group 1, glenohu-meral arthroscopy did not lead to the discovery of specific elements except in two cases where it identified partial tear of the deep aspect of the supraspinatus. Acromioplasty was never performed. Discussion-Conclusion: Systematic glenohumeral arthros-copy is not warranted in patients undergoing treatment for calcified tendinopathy. The fact that glenohumeral exploration did not disclose any particular element and had no effect on healing and capsulitis rates favours the use of a subacromial approach alone

Introduction: Achilles tendinopathy is a source of significant pain and disability. While many patients respond to non-operative treatment, a proportion will require operative treatment. Both open decompression and percutaneous longitudinal tenotomy have been described. We describe a new technique and present the results of percutaneous circumferential decompression of the tendon, dividing adhesions between the paratenon and the tendon. Methods: We followed up 10 patients for a mean of 10 months (5–19) post operatively. They were scored pre and post operatively using the tegner activity score, the puddu score and an analogue pain score. The functional result was also assessed with the SF12 questionnaire. Results: All patients reported significant improvements in pain (p=0.007), tegner (p=0.007) and puddu (p=0.005) scores. They would all undergo the procedure again. The SF12 scores were not significantly different from a normal population. Discussion: We believe that this technique addresses the underlying pathology, giving excellent results without the potential complications of an open decompression

Tendinopathy is a debilitating musculoskeletal condition which can cause significant pain and lead to complete rupture of the tendon, which often requires surgical repair. Due in part to the large spectrum of tendon pathologies, these disorders continue to be a clinical challenge. Animal models are often used in this field of research as they offer an attractive framework to examine the cascade of processes that occur throughout both tendon pathology and repair. This review discusses the structural, mechanical, and biological changes that occur throughout tendon pathology in animal models, as well as strategies for the improvement of tendon healing. Cite this article: Bone Joint Res 2014;3:193–202

Background. The Plantaris Longus Tendon (PLT) may be implicated in Achilles (AT) tendinopathy. Different mechanical characteristics may be the cause. This study is designed to measure these. Methods. Six PLT and six AT were harvested from frozen cadavers (aged 65-88). Samples were stretched to failure using a Minimat 2000(tm) (Rheometric Scientific Inc.). Force and elongation were recorded. Calculated tangent stiffness, failure stress and strain were obtained. Averaged mechanical properties were compared using paired, one-tailed t-tests. Results. Mean stiffness was higher (p<0.001) in the PLT, measuring 5.71 N/mm (4.68-6.64), compared with 1.73 N/mm (1.40-2.22) in AT. Failure stress was also higher (p<0.01) in PLT: 1.42 N/mm. 2. (0.86-2.23) AT: 0.20 N/mm. 2. (0.16-0.25). Failure strain was less (p<0.05) in PLT: 14.1% (11.5-16.8) than AT: 21.8% (14.9-37.9). Conclusions. The PLT is stiffer, stronger than AT, demonstrating potential for relative movement under load. The stiffer PLT could tether AT and initiate an inflammatory response

Summary Statement. The effects of local glucocorticoid on tendon appear broadly negative and this supports the emerging clinical evidence which points toward significant long term harms associated with this treatment modality. Introduction. The use of locally administered glucocorticoid is widespread in the treatment of painful tendinopathy. Despite evidence of short term benefit, the emerging evidence points toward significant long term harms associated with this method of treatment, including an increased risk of recurrence, rupture and worsened clinical outcomes (1, 2). Our primary purpose was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells. Methods. We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. Only studies analysing the effects of locally administered glucocorticoid on tendon tissue or tendon cells with adequate controls were included. Specific attention was paid to histological and biomechanical findings. Inclusion was agreed upon by two independent researchers after review of abstracts or full text. The search yielded 4424 results, of which 42 met the inclusion criteria. The final 42 articles consisted of 13 human in vitro studies, 15 animal in vivo studies and 14 animal in vitro studies. Results. Due to study heterogeneity, statistical pooling or meta-analysis of data was not possible. The results are therefore described qualitatively. Histologically, there was a loss of collagen structure (5 studies) and an increase in collagen necrosis (4 studies). The proliferation and viability of fibroblasts was reduced (11 studies). An increased inflammatory cell infiltrate was shown in 3 animal in vivo studies, while an increased fibroblast infiltrate was seen in 2 studies. Fibroblast migration was reduced in 2 in vitro studies. Collagen synthesis was reduced in 13 studies. An increased ratio of type 3 to type 1 Collagen was shown in 2 studies. Apoptosis was unaffected in 2 studies. 19 studies investigated the mechanical properties of tendon. Of these 7 showed deterioration in mechanical properties, 4 showed an improvement and 8 showed no difference. Discussion/Conclusion. Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, such as reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by animal in vivo studies. The mechanical effects are equivocal. This review supports emerging clinical evidence showing significant long term harms associated with glucocorticoid injections. There is clearly a significant need for better designed human trials with appropriate blinding and control arms to investigate the effects of glucocorticoid on both clinical outcomes and characteristics of tendon tissue

Aims: We studied the prevalence of calciþc tendinopathy in asymptomatic subjects and the relationship between calciþc deposits and the anatomopathological characteristic of coracoacromial arch. Methods: 222 right-handed volunteers underwent x-ray examination of the right shoulder. We measured the acromiohumeral distance (AHD) and evaluated the acromion shape and the degenerative changes of the GH and AC joints. We measured the size of the deposits and classiþed the calciþcations based on their location, shape and neatness. The subjects with deposits were clinically evaluated and underwent a second x-ray study after 14 months. Results: 11 subjects (5%) had calciþcation. The latter was in the substance of supraspinatus in 5(mean age 45 yrs) and at cuff insertion in 6 (66 yrs). The deposits measured 0.7±0.3cm (avg). There were 3 linear and 2 beanlike intratendinous calciþcations and 5 linear and 1 beanlike deposits at tendon insertion. Calciþcations had well-deþned margins. AHD, acromion shape, arthritic of the GH or AC joint were unrelated to the presence of calciþcations. No subject showed evidence of cuff tear. Intratendinous deposit decreased in size in 2 cases and disappeared in 1. Conclusions: 5% of asymptomatic subjects have calciþcations. Calciþcations are always small and well-deþned. Morphology and changes of the cora-coacromial arch or the GH or AC joint donñt inßuence the deposition of calcium. Our study suggests that calciþcations may decrease in size or disappear without completion of Uhthoffñs cycle

Introduction. Numerous risk factors have been identified for patellar tendinopathy (PT), often in small population studies. The aim was to use an online questionnaire internationally to generate a large database and identify significant risk factors. Materials and Methods. Subjects were recruited from England, Spain and Italy with the questionnaire available in all three languages, with the questionnaire previously having been validated by Morton et al. (2014) as to be suitable for self-administration. The questionnaire can be viewed at: . http://patellartendinopathyquestionnaire.blogspot.co.uk/. (English), . http://tendinopatiarotuliana.blogspot.co.uk/. (Spanish) and . http://tendinopatiarotulea.blogspot.co.uk/. (Italian). All data was anonymised and password protected. 825 data sets were collected with 23.4% having clinically diagnosed PT. Results. Eight risk factors were included in the analysis based on a purposeful selection procedure: gender, hours of training, hamstring flexibility, previous patellar tendon rupture, previous knee injury, current/previous back pain, family history and age. To be female was found to be positively associated with PT, suggesting being female is protective (odds ratio (OR) = 0.70, 95% CI: 0.49–1.00, p=0.05). As hours of training increased the association with PT became stronger so that training >20 hours a week had a very significant OR of 8.94 (95%CI: 4.68–17.08, p<0.05), the most significant OR calculated. There was an association between a previous knee injury and PT (OR=2.10, 95% CI: 1.45–3.04, p<0.05) and having self-reported flexible hamstrings suggested some protection from PT (OR=0.61, 95% CI0.38–0.97, p=0.04). There was a trend towards association for back pain (OR=1.45, 95% CI: 0.99–2.14, p=0.06) and a family history of tendon problems (OR=1.51, 95% CI: 0.96–2.37, p=0.08). Discussion. Risk factors have been identified that are potentially modifiable in order to inform prevention and rehabilitation programmes; future research is required to establish causal relationships. Certain risk factors require investigation as they are not currently recognised in the literature

Background: The results of operative management for distal tibialis anterior tendinopathy (DTAT) without rupture have not previously been described in the orthopaedic literature. We present the results of 15 operative procedures. Method: Of 40 patients diagnosed clinically and radiographically with DTAT, we reviewed the 13 patients who underwent surgery for failure of non-operative management. Assessment included pre and postoperative AOFAS midfoot scores, clinical examination and postoperative VAS pain scoring. Results: Twelve women (13 feet) and one man (2 feet) underwent surgery. The mean age at surgery was 59 years. The mean duration of symptoms prior to surgery was 1 year. The mean pre-operative AOFAS score was 53. Preoperative MRI showed tendinosis with longitudinal split tears in 10 tendons and tendinosis alone in two tendons. Seven of the 15 cases showed some associated degenerative changes of the midfoot. Six tendons were simply debrided and the insertion reinforced with a suture anchor. Nine tendons were augmented with an Extensor Hallucis Longus (EHL) transfer into the medial cuneiform. All patients improved postoperatively, with a mean improvement in AOFAS score of 32 and the mean postoperative pain VAS of 1.0 out of 10, at a mean follow-up of 24 months. Three patients underwent concomitant procedures on the same foot. Four of the nine treated with EHL transfer have some symptomatic hallux interphalangeal joint extensor lag. In seven cases the patient was completely satisfied. Five were satisfied with minor reservations. Of the three that were dissatisfied, two underwent subsequent surgery improving their symptoms. The third, though pain free, was troubled by her toe-catching when walking barefoot. No patient regretted having had the surgery. Conclusion: Debridement and repair of DTAT, with EHL augmentation for greater than 50% tendon involvement, provides a high level of patient satisfaction if non-operative management fails

Introduction: Achilles tendinopathy (AT) is the most common over use syndrome of the lower limb. One of the simple operations performed for this condition is “Multiple longitudinal tenotomies”. This can be performed by either percutaneous or open methods. We compared the outcome of percutaneous versus open method of multiple longitudinal tenotomies for this condition. Methods and materials: It is a retrospective study of patients operated for AT in our hospital from 1997 to 2008. Total of 43 patients. Twenty had percutaneous and 23 had open tenotomies. All of them had a trial of non-operative treatment prior to surgery, in the form of analgesia, physiotherapy, heel inserts, and ultrasound therapy. Data was collected from patient records and by telephonic questionnaire of the patients. Data collected includes pre and postoperative pain scores on a scale of 0–10, duration of symptoms, patient satisfaction scores (0–10) and complications. This questionnaire also included limitation to walk, run, going up/down the stairs, work and sporting activities. Results: In the percutaneous group the mean pre and postoperative pain scores were 8.79 and 2.07 (p value 0.000). In the open group the values were 8.65 and 1.75 (p value 0.000). The mean satisfaction scores in the percutaneous and open groups were 8.25 (range 3–10) and 8.14(range2–10) respectively. The patient satisfaction scores were not significantly different between the two groups (p value 0.942). In the percutaneous group there was one recurrence and in one patient there was no symptomatic relief. In the open group there were 2 superficial infections, which settled with antibiotics and a wound breakdown, which in addition required debridement and eventually healed by secondary intension. Conclusions: Both percutaneous and open methods of longitudinal tenotomies resulted in significant symptomatic relief and good patient satisfaction scores. Although the outcomes of both groups were comparable the percutanous method has an added advantage of less complications and simplicity of the procedure

Introduction: A recent clinical study has suggested that topical GTN may improve the outcome of non-insertional Achilles tendinopathy. The mechanism for this improvement is obscure but is thought to be due to modulation of local nitric oxide (NO) levels. The purpose of this study was to assess the clinical and histological results of topical GTN for non-insertional Achilles tendonitis. Methods: 40 patients with non-insertional Achilles tendonitis underwent standard non¬operative therapy. 20 patients also used topical GTN daily. AOFAS, AOS visual analogue scores and SF36 forms were completed pre-treatment and 3 months later. Patients who failed conservative treatment and underwent surgery had histological examination of the Achilles tendon and histochemical analysis for isomers of NOS (eNOS and iNOS) as a marker of NO production. Results: There was an overall improvement in symptoms in both groups but no significant difference in the improvement between them – there was no additional benefit in using GTN patches. 4 patients also had to stop using patches within 3 weeks because of headaches. Histological examination did not show any difference in collagen synthesis or remodelling between the 2 groups and there was no evidence of stimulated wound fibroblasts in the GTN group. There was no difference between the groups in the expression of eNOS or iNOS. Conclusion: This study fails to demonstrate any improvement in symptoms when using GTN patches. There is no histological evidence that GTN promotes degenerate tendon to stimulate wound fibroblasts and increase collagen synthesis and remodelling. GTN patches do not appear to modulate the expression of NOS enzymes in diseased Achilles tendon. The use of GTN patches in the treatment of non-insertional Achilles tendonitis remains questionable and the role of NO as a mediator of inflammatory response remains elusive

Introduction: A recent clinical study has suggested that topical GTN may improve the outcome of non-insertional Achilles tendinopathy. The mechanism for this improvement is obscure but is thought to be due to modulation of local nitric oxide (NO) levels. The purpose of this study was to assess the clinical and histological results of topical GTN for non-insertional Achilles tendonitis. Methods: 40 patients with non-insertional Achilles tendonitis underwent standard non-operative therapy. 20 patients also used topical GTN daily. AOFAS, AOS visual analogue scores and SF36 forms were completed pre-treatment and 3 months later. Patients who failed conservative treatment and underwent surgery had histological examination of achilles tendon and histochemical analysis for isomers of NOS (eNOS and iNOS) as a marker of NO production. Results: There was an overall improvement in symptoms in both groups but no significant difference in the improvement bewtween them – there was no additional benefit in using GTN patches. 4 patients also had to stop using patches within 3 weeks because of headaches. Histological examination did not show any difference in collagen synthesis or remodelling between the 2 groups and there was no evidence of stimulated wound fibroblasts in the GTN group. There was no difference between the groups in the expression of eNOS or iNOS. Conclusion: This study fails to demonstrate any improvement in symptoms when using GTN patches. There is no histological evidence that GTN promotes degenerate tendon to stimulate wound fibroblasts and increase collagen synthesis and remodelling. GTN patches do not appear to modulate the expression of NOS enzymes in diseased Achilles tendon. The use of GTN patches in the treatment of non-insertional Achilles tendonitis remains questionable and the role of NO as a mediator of inflammatory response remains elusive

Introduction. The operative management for Distal Tibialis Anterior Tendinopathy (DTAT) without rupture has not previously been described. We present 15 cases. Method. of 39 patients diagnosed clinically and radiographically with DTAT, we reviewed the 13 patients who underwent surgery for failure of non-operative management. Assessment included pre and post-operative AOFAS midfoot scoring, clinical examination and post-operative VAS pain scoring. Results. Twelve women (13 feet) and one man (two feet) underwent surgery. Mean age at surgery was 59 years (42 to 76 years). The mean duration of symptoms prior to surgery was one year (5 to 25 months). The mean pre-operative AOFAS score was 50 (23 to 75). Pre-operative MRI showed tendinosis in six tendons and tendinosis with longitudinal split tears in nine tendons. Five of the 14 cases showed some associated degenerative changes of the midfoot. Six tendons were simply debrided and the insertion reinforced with a suture anchor. Nine tendons were augmented with an Extensor Hallucis Longus (EHL) transfer into the medial cuneiform. The mean improvement in AOFAS score was 35 (4 to 57), with mean post-operative pain VAS of 1 (0 to 6.7) at a mean follow-up of 24 months (three to 65). Two patients underwent concomitant procedures on the same foot. Four of the nine treated with EHL transfer have some symptomatic hallux interphalangeal joint extensor lag. In seven cases the patient was completely satisfied. Five were satisfied with minor reservations. Of the three that were dissatisfied, two underwent subsequent surgery improving their symptoms. The third, though pain-free, was troubled by her toe catching when walking barefoot. No patients regret having had the surgery. Conclusion. Debridement and repair of DTAT, with EHL augmentation for greater than 50% tendon involvement, provides a high level of patient satisfaction if non-operative management fails

Purpose: Insertional calcific Achilles tendinosis is a painful, frequently disabling, condition. The longitudinal and radial alignment of the angiosomes of the posterior region of the leg makes a straight posterior midline approach logical. The safety of the posterior midline approach and the outcome of a central tendon splitting approach associated with a Strayer procedure to treat this condition was evaluated. Method: A retrospective review of a consecutive cohort of a single surgeon was performed. All patients had failed conservative treatment and all patients were primary cases. Forty-seven patients (48 heels) were treated over a 11-year period for chronic insertional Achilles tendinosis. All patients underwent a midline posterior splitting approach, debridment of the bursae, resection of the haglund deformity, partial Achilles detachment, debridement, reinsertion with bone anchor associated with a proximal gatrocnemius recession (strayer procedure) through a second midline incision. The average age was 59 years old (39–75), co-morbidities included four smokers and one diabetic patient. The average followup was 54 months (15–144). All patients answered pre-op and latest follow up AOFAS questionnaire, satisfaction rate and complications were reviewed. Results: Satisfaction rate was 100%. AOFAS score improved significantly from 59 (36–80) preop to 97 (90–100) at the latest follow-up. Complications included one superficial infection and one sural nerve paresthesia. There were no major complications. Conclusion: Achilles insertional tendinopathy treated by a posterior midline approach is a safe and reliable procedure. The procedure was associated with high patient satisfaction rate and excellent outcome

Purpose: Endoscopy provides an attractive alternative to open surgery for diagnostic and therapeutic purposes in patients with ankle tendon disease. Early work was published by Van Dijk in 1994. Material and methods: Twenty patients (mean age 34.7 years, range 20–59 years), 16 with posttraumatic lesions, underwent 22 tendinoscopy procedures using a slightly modified technique with a 4.5 optical. The procedures, conducted under general anaesthesia, were performed to explore fibular (n=15), posterior tibial (n=6), and anterior tibial (n=1) tendons. Prospective follow-up was at least six months (6 – 30). Preoperatively, all patients presented more or less localised pain with signs of tendon suffering. Fifteen had undergone prior explorations (ultrasound=4, MRI=7, CT scan=1, MRI+ultrasound=3) which had not revealed any anomaly in seven. Results: Peritendinous adherences were observed intra-operatively in 18 cases with inflammatory reactions requiring resection in 13. A lesion of the tendon itself was found in seven cases-fissure (n=2), superficial dilaceration (n=2), induration (n=2), strangulation (n=1)-which required specific cure with forceps or motorised instrumentation. No explanation of the pain could be identified in one patient. Postoperatively, 17 patient achieved complete pain relief which persisted for at least six months. At last follow-up, one patient had not been reviewed, twelve were totally pain free and five had developed associated symptoms (cracking, swelling). Overall, four patients were very satisfied, eight were satisfied, four were disappointed, and three were dissatisfied (no improvement). There were no signs of worsening and no complications directly related to the method. Conclusion: These results of early experience in France are less satisfactory than those reported by Van Dijk who had 80% good results for 85 tendinoscopic procedures in 70 patients. They do however confirm the usefulness of this technique for the management of patients with tenosynovitis, adherences, and partial ruptures of the ankle tendons which cannot always be identified with classical imaging techniques. Definitive evaluation will require analysis of a larger series of well selected patients

Aims

A revision for periprosthetic joint infection (PJI) in total hip arthroplasty (THA) has a major effect on the patient’s quality of life, including walking capacity. The objective of this case control study was to investigate the histological and ultrastructural changes to the gluteus medius tendon (GMED) in patients revised due to a PJI, and to compare it with revision THAs without infection performed using the same lateral approach.

This paper describes the current views on the pathology of lesions of the tendon of the long head of biceps and their management. Their diagnosis is described and their surgical management classified, with details of the techniques employed.

The cause of elbow tendinosis is most likely a combination of mechanical overloading and abnormal microvascular responses. Numerous methods of treatment have been advocated. In this study, we evaluated the use of platelet-rich plasma (PRP) as a treatment for resistant epicondylitis. The rationale for using platelets is that they participate predominantly in the early inflammation phases and degranulation. They constitute a reservoir of critical growth factors and cytokines which when placed directly into the damaged tissue, may govern and regulate the tissue healing process. We looked at 25 patients (19 with lateral and 6 with medial) who failed to improve after physiotherapy, cortisone injections and application of epicondylar clasps and assessed the efficacy of platelet-rich plasma injections using Gravitational platelet separation system (GPS). The cohort of patients included over a period of three years had physiotherapy, stretches, epicondylar clasp and an average of 2.9steroid injections (1–6) before having a PRP injection.

The mean patient age was 43 years ranging between 24 and 54. There were 11 men and 14 women. The study included 19 patients with lateral epicondylitis and 6 patients with symptoms on the medial side. The ratio between dominant and nondominant side was according to the literature: 76%.

The quick DASH scores imroved by 14% on an average in the first 3 months and further 26% in the following 9 months. 4 patients needed reintervention, 3 lateral and 1 medial and had surgical release between 6 and 12 months. 2 of them had reinjections before surgery. No local infections except mild inflammation and no systemic effects were noted.

Within the limitations of being a case series and limited follow-up PRP injections provided a safe and progressive benefit over a period of 1 year in refractory cases, providing a good nonoperative alternative.

Introduction

The pathogenesis of rotator cuff disease (RCD) is complex and not fully understood. This systematic review set out to summarise the histological and molecular changes that occur throughout the spectrum of RCD.

Lateral epicondylitis, or ’tennis elbow’, is a common condition that usually affects patients between 35 and 55 years of age. It is generally self-limiting, but in some patients it may continue to cause persistent symptoms, which can be refractory to treatment. This review discusses the mechanism of disease, symptoms and signs, investigations, current management protocols and potential new treatments.

Cite this article: Bone Joint J 2013;95-B:1158–64.

Aims. Achilles tendon re-rupture (ATRR) poses a significant risk of postoperative complication, even after a successful initial surgical repair. This study aimed to identify risk factors associated with Achilles tendon re-rupture following operative fixation. Methods. This retrospective cohort study analyzed a total of 43,287 patients from national health claims data spanning 2008 to 2018, focusing on patients who underwent surgical treatment for primary Achilles tendon rupture. Short-term ATRR was defined as cases that required revision surgery occurring between six weeks and one year after the initial surgical repair, while omitting cases with simultaneous infection or skin necrosis. Variables such as age, sex, the presence of Achilles tendinopathy, and comorbidities were systematically collected for the analysis. We employed multivariate stepwise logistic regression to identify potential risk factors associated with short-term ATRR. Results. From 2009 to 2018, the short-term re-rupture rate for Achilles tendon surgeries was 2.14%. Risk factors included male sex, younger age, and the presence of Achilles tendinopathy. Conclusion. This large-scale, big-data study reaffirmed known risk factors for short-term Achilles tendon re-rupture, specifically identifying male sex and younger age. Moreover, this study discovered that a prior history of Achilles tendinopathy emerges as an independent risk factor for re-rupture, even following initial operative fixation. Cite this article: Bone Joint Res 2024;13(7):315–320

Psoas tendinopathy is a potential cause of groin pain after primary total hip arthroplasty (THA). The direct anterior approach (DAA) is becoming increasingly popular as the standard approach for primary THA due to being a muscle preserving technique. It is unclear what the prevalence is for the development of psoas-related pain after DAA THA, how this can influence patient reported outcome, and which risk factors can be identified. This retrospective case control study of prospectively recorded data evaluated 1784 patients who underwent 2087 primary DAA THA procedures between January 2017 and September 2019. Psoas tendinopathy was defined as (1) persistence of groin pain after DAA THA and was triggered by active hip flexion, (2) exclusion of other causes such as dislocation, infection, implant loosening or (occult) fractures, and (3) a positive response to an image-guided injection with xylocaine and steroid into the psoas tendon sheath. Complication-, re-operation rates, and patient-reported outcome measures (PROMs) were measured. Forty-three patients (45 hips; 2.2%) were diagnosed with psoas tendinopathy according to the above-described criteria. The mean age of patients who developed psoas tendinopathy was 50.8±11.7 years, which was significantly lower than the mean age of patients without psoas pain (62.4±12.7y; p<0.001). Patients with primary hip osteoarthritis were significantly less likely to develop psoas tendinopathy (14/1207; 1.2%) in comparison to patients with secondary hip osteoarthritis to dysplasia (18/501; 3.6%) (p<0.001) or FAI (12/305; 3.9%) (p<0.001). Patients with psoas tendinopathy had significantly lower PROM scores at 6 weeks and 1 year follow-up. Psoas tendinopathy was present in 2.2% after DAA THA. Younger age and secondary osteoarthritis due to dysplasia or FAI were risk factors for the development of psoas tendinopathy. Post-operatively, patients with psoas tendinopathy often also presented with low back pain and lateral trochanteric pain. Psoas tendinopathy had an important influence on the evolution of PROM scores

The December 2022 Shoulder & Elbow Roundup. 360. looks at: Biceps tenotomy versus soft-tissue tenodesis in females aged 60 years and older with rotator cuff tears; Resistance training combined with corticosteroid injections or tendon needling in patients with lateral elbow tendinopathy; Two-year functional outcomes of completely displaced midshaft clavicle fractures in adolescents; Patients who undergo rotator cuff repair can safely return to driving at two weeks postoperatively; Are two plates better than one? A systematic review of dual plating for acute midshaft clavicle fractures; Treatment of acute distal biceps tendon ruptures; Rotator cuff tendinopathy: disability associated with depression rather than pathology severity; Coonrad-Morrey total elbow arthroplasty implications in young patients with post-traumatic sequelae

Tendinopathy is the most common form of chronic tendon disorders, accounting for up 30% of all musculoskeletal clinic visits [1]. In tendon disease, the largely avascular tendon tissue often becomes hypervascularized and fibrotic [2]. As blood vessel growth and angiogenic signaling molecules are often induced by the lack of adequate nutrients and oxygen, hypoxic signaling is speculated to be a root cause of tendon neovascularization and tendinopathy [3,4,5]. However, how the vascular switch is initiated in tendons, and how vascularization contributes to tendon pathology remains unknown. In this talk, we provide evidence that HIF-1α is implicated in tendon disease and HIF-1α stabilization in human tendon cells induces vascular recruitment of endothelial cells via VEGFa secretion. More interesting, HIF-1α stabilization in tendon cells in vivo, seems to recapitulate all main features of fibrotic human tendon disease, including vascular ingrowth, matrix disorganization, changes in tissue mechanics, cell proliferation and innervation. Surprisingly, in vivo knock-out of VEGFa rescued angiogenesis in the tendon core but it did not affect tendon mechanical properties and tissue pathophysiological changes, suggesting that blood vessels ingrowth might not be a primary cause but a consequence of HIF-1α activation

As high incidences of tendinopathies are observed particularly in those who intensively use their tendons, we assume that pathological changes are caused, at least partially, by mechanical overload. This has led to the so-called overload hypothesis, explaining the development of tendinopathies by structural failure resulting from excessive load. At the same time, tendon loading is an important part in tendon rehabilitation. Currently, exercise treatment approaches such as eccentric training or heavy load resistance training are widely applied in tendinopathy rehabilitation, with good clinical results such as an improvement in function and a reduction in pain. Particularly those rehabilitative approaches which impose high strains on the tendon may induce an adaptation of the tendon's mechanical properties such as increased tendon stiffness. An increased tendon stiffness is often interpreted as desirable, as it may protect the tendon from overloading and thus prevent future strain injuries. However, the tendinopathic tendon is not necessarily less stiff than the tendon in the contralateral leg and an improvement in tendon stiffness is not necessarily accompanied by an improvement in tendon pain or function. In addition, metabolic factors, resulting e.g. in low-level systemic inflammation, may contribute to pathological tendon tissue changes and are not necessarily affected by an exercise program, while nutritional interventions or dietary supplements may potentially affect tendon cell metabolism. Indeed, dietary supplements have been introduced as an additional therapeutic approach in the treatment of tendinopathies in recent years, and their positive curative effects have been reported for both the general population and athletes. In the management of tendinopathies, it may thus be advisable if therapeutic approaches aim to address both tendon mechanics and tendon metabolism for better treatment effectiveness and a sustainable improvement in pain and function

The October 2023 Sports Roundup. 360. looks at: Extensor mechanism disruption in the treatment of dislocated and multiligament knee injuries; Treatment of knee osteoarthritis with injection of stem cells; Corticosteroid injection plus exercise or exercise alone as adjuvants for patients with plantar fasciitis?; Generalized joint hypermobility and a second ACL injury?; The VISA-A ((sedentary) questionnaire for Achilles tendinopathy?

Gluteal Tendinopathy is a poorly understood condition that predominantly affects post-menopausal women. It causes lateral hip pain, worse when lying on the affected side or when walking up a hill or stairs. It has been labelled ˜Greater Trochanteric Pain Syndrome” a name that recognises the lack of understanding of the condition. Surgical reconstruction of the gluteal cuff is well established and has been undertaken numerous times over the last 16 years by the senior author (AJL). However, the quality of collagen in the tendons can be very poor and this leads to compromised results. We present the results of gluteal cuff reconstruction combined with augmentation using a bioinductive implant. 14 patients (11 female, 3 male; mean age 74.2 ± 6.3 years) with significant symptoms secondary to gluteal tendinopathy that had failed conservative treatment (ultrasound guided injection and structured physiotherapy) underwent surgical reconstruction by the senior author using an open approach. In all cases the iliotibial band was lengthened and the trochanteric bursa excised. The gluteal cuff was reattached using Healicoil anchors (3–5×4.75mm anchors; single anchors but double row repair) and then augmented using a Regeneten patch. Patients were mobilised fully weight bearing post-operatively but were asked to use crutches until they were no longer limping. All had structured post-surgery rehabilitation courtesy of trained physiotherapists. There were no post-operative complications and all patients reported an improvement in pain levels (Visual Analogue Scale 7.8 pre-op; 2.6 post-op) and functional levels (UCLA Activity Score 3.5 pre-op; 7.1 post-op) at 6 months post surgery. Surgery for gluteal tendinopathy produces good outcomes and the use of Regeneten as an augment for poor quality collagen is seemingly a safe, helpful addition. Further comparative studies would help clarify this

Introduction and Objective. Chronic tendinopathy is a multifactorial disease and a common problem in both, athletes and the general population. Mechanical overload and in addition old age, adiposity, and metabolic disorders are among the risk factors for chronic tendinopathy but their role in the pathogenesis is not yet unequivocally clarified. Materials and Methods. Achilles tendons of young (10 weeks) and old (100 weeks) female rats bred for high (HCR) and low (LCR) intrinsic aerobic exercise capacity were investigated. Both Achilles tendons of 28 rats were included and groups were young HCR, young LCR, old HCR, and old LCR (n = 7 tendons per group/method). In this rat model, genetically determined aerobic exercise capacity is associated with a certain phenotype as LCR show higher body weight and metabolic dysfunctions in comparison to HCR. Quantitative real-time PCR (qPCR) was used to evaluate alterations in gene expression. For histological analysis, semi-automated image analysis and histological scoring were performed. Results. Age-related downregulation of tenocyte marker genes (Tenomodulin), genes related to matrix modelling and remodeling (Collagen type 1, Collagen type 3, Elastin, Biglycan, Fibronectin, Tenascin C), and Transforming growth factor beta 3 (Tgfb3) were detected in tendons from HCR and LCR. Furthermore, inflammatory marker Cyclooxygenase 2 (Cox2) was downregulated, while Microsomal prostaglandin E synthase 2 (Ptges2) was upregulated in tendons from old HCR and old LCR. No significant alteration was seen in Interleukin 6 (Il6), Interleukin 1 beta (Il1b), and Tumor necrosis factor alpha (Tnfa). Histological analysis revealed that Achilles tendons of old rats had fewer and more elongated tenocyte nuclei compared to young rats, indicating a reduced metabolic activity. Even though higher content of glycosaminoglycans as a sign of degeneration was found in tendons of old HCR and LCR, no further signs of tendinopathy were detectable in histological evaluation. Conclusions. Overall, aging seems to play a prominent role in molecular and structural alterations of Achilles tendon tissue, while low intrinsic exercise capacity did not cause any changes. Even though tendinopathy was not present in any of the groups, some of the shown age-related changes correspond to single characteristics of chronic tendon disease. This study gives an insight into tendon aging and its contribution to molecular and cellular changes in Achilles tendon tissue

Introduction. Achilles tendon rupture (ATR) account for 10.7% of all tendon and ligament injuries and causes lasting muscular deficits and have a profound impact on patients’ quality of life. 1,2. The incidence, characteristics and management of ATR in the United Kingdom is poorly understood. Method. Data was collected prospectively from University Hospitals of Leicester Emergency Department (ED) between January 2016 and December 2020 and analysed retrospectively. The medical records were reviewed to determine management protocols (surgical/non-surgical) and limited mobilisation (VACOped™ boot) duration. Leicestershire population data was taken from Leicestershire County Council demography report. Findings. 277 individuals were diagnosed with an ATR during the 4-year period. The mean (SD) annual incidence was 56 (±6) ATR. An incidence rate of 8.02 per 100,000 people per annum. The average characteristics of those experiencing an ATR is male (78.3%), 46.8yrs old (±14.4), body mass index 29.1 (±6.3). Median (IQR) number of comorbidities 1 (2) and duration to present to ED was 0 days (1). The main mechanism of rupture was sporting activity (62.1%). 97.4% were non-surgically managed using a limited mobilisation boot (VACOped). The boot was worn for an average of 62.6 days (±8.9). 94 participants provided pre-ATR Achilles symptoms data. 16% (n=15/94) of participants reported a previous contralateral ATR. 7.4% reported a re-rupture (n=7/94). 15.4% (n=14/91) reported an Achilles tendinopathy on the ipsilateral side prior to ATR. 7.7% (n=7/91) reported bilateral Achilles tendinopathy and 1.1% (n=1/91) reported contralateral Achilles tendinopathy prior to ATR. Conclusion. The incidence of ATR is 8.02 cases per 100,000 people per annum. This is the first UK data on ATR incidence. Most ATR were managed non-surgically in this cohort. The majority of ruptures occurred during sporting activity. Those that had previous Achilles symptoms (24.2%) indicate tendons are not always asymptomatic prior to ATR

Tenotomy of the iliopsoas tendon has been described as an effective procedure to treat refractive groin pain induced by iliopsoas tendinitis. However, the procedure forces the rectus femoris to act as the primary hip flexor and little is known about the long-term effects of this procedure on the peri-articular muscle envelope (PAME). Studies suggest that iliopsoas tenotomy results in atrophy of the iliopsoas and decreased hip flexion strength with poorer outcomes, increasing the susceptibility for secondary tendinopathy. The aim of this study is to describe changes in the PAME following psoas release. All patients who presented for clinical examination at our hospital between 2016 and 2021 were retrospectively reviewed. Patients who presented after psoas tenotomy with groin pain and who were unable to actively lift the leg against gravity, were included. Pelvic MRI was taken. Qualitative muscle evaluation was done with the Quartile classification system. Quantitative muscle evaluation was done by establishing the cross-sectional area (CSA). Two independent observers evaluated the ipsi- and contralateral PAME twice. The muscles were evaluated on the level: iliacus, psoas, gluteus minimus-medius-maximus, rectus femoris, tensor fasciae lata, piriformis, obturator externus and internus. For the qualitative evaluation, the intra- and inter-observer reliability was calculated by using kappastatistics. A Bland-Altman analysis was used to evaluate the intra- and inter-observer reliability for the quantitative evaluation. The Wilcoxon test was used to evaluate the changes between the ipsi- and contra-lateral side. 17 patients were included in the study. Following psoas tenotomy, CSA reduced in the ipsilateral gluteus maximus, if compared with the contralateral side. Fatty degeneration occurred in the tensor fascia latae. Both CSA reduction and fatty degeneration was seen for psoas, iliacus, gluteus minimus, piriformis, obturator externus and internus. No CSA reduction and fatty degeneration was seen for gluteus medius and rectus femoris. Conclusions/Discussion. Following psoas tenotomy, the PAME of the hip shows atrophy and fatty degeneration. These changes can lead to detrimental functional problems and may be associated with debilitating rectus femoris tendinopathy. In patients with psoas tendinopathy, some caution is advised when considering an iliopsoas tenotomy

The December 2022 Sports Roundup. 360. looks at: Anterior cruciate ligament (ACL) repair with dynamic intraligamentary stabilization or anterior ACL at five years?; Femoroacetabular impingement in mild osteoarthritis: is hip arthroscopy the answer?; Steroids in Achilles tendinopathy: A randomized trial

The June 2024 Foot & Ankle Roundup. 360. looks at: First MTPJ fusion in young versus old patients; Minimally invasive calcaneum Zadek osteotomy and the effect of sequential burr passes; Comparison between Achilles tendon reinsertion and dorsal closing wedge calcaneal osteotomy for the treatment of insertional Achilles tendinopathy; Revision ankle arthroplasty – is it worthwhile?; Tibiotalocalcaneal arthrodesis or below-knee amputation – salvage or sacrifice?; Fusion or replacement for hallux rigidus?

Tendinopathy is a disease associated with pain and tendon degeneration, leading to a decreased range of motion and an increased risk of tendon rupture. The etiology of this frequent disease is still unknown. In other musculoskeletal tissues like cartilage and intervertebral discs, transient receptor potential channels (TRP- channels) were shown to play a major role in the progression of degeneration. Due to their responsiveness to a wide range of stimuli like temperature, pH, osmolarity and mechanical load, they are potentially relevant factors in tendon degeneration as well. We therefore hypothesize that TRP- channels are expressed in tendon cells and respond to degeneration inducing stimuli. By immunohistochemistry, qRT-PCR and western blot analyses, we found three TRP channel members, belonging to the vanilloid (TRPV), and ankyrin (TRPA) subfamily, respectively, to be expressed in healthy human tendon tissue as well as in rodent tendon, with expression being located to cells within the dense tendon proper, as well as to endotenon resident cells. In vitro-inflammatory and ex vivo-mechanical stimulation led to a significant upregulation of TRPA1 expression in tendon cells, which correlates well with the fact that TRPA1 is considered as mechanosensitive channel being sensitized by inflammatory mediators. This is the first description of TRP- channels in human and rodent tendon. As these channels are pharmacologically targetable by both agonists and antagonists, they may represent a promising target for novel treatments of tendinopathy

MicroRNA (miR) delivery to regulate chronic inflammation hold extraordinary promise, with new therapeutic possibilities emanating from their ability to fine-tune multiple target gene regulation pathways which is an important factor in controlling aberrant inflammatory reactions in complex multifactorial disease. However, several hurdles have prevented advancements in miR-based therapies. These include off-target effects of miRs, limited trafficking, and inefficient delivery. We propose a magnetically guided nanocarrier to transport therapeutically relevant miRs to assist self- resolving inflammation processes at injury sites and reduce the impact of chronic inflammation- related diseases such as tendinopathies. The high prevalence, significant socio-economic burden and increasing recognition of dysregulated immune mediated pathways in tendon disease provide a compelling rationale for exploring inflammation-targeting strategies as novel treatments in this condition. By combining cationic polymers, miR species (e.g., miR 29a, miR155 antagonist), and magnetic nanoparticles in the form of magnetoplexes with highly efficient magnetofection procedures, we developed inexpensive, easy-to-fabricate, and biocompatible systems with competent miR-binding and fast cellular uptake into different types of human cells, namely macrophages and tendon-derived cells. The system was shown to be cell-compatible and to successfully modulate the expression and production of inflammatory markers in tendon cells, with evidence of functional pro-healing changes in immune cell phenotypes. Hence, magnetoplexes represent a simple, safe, and non-viral nanoplatform that enables contactless miR delivery and high- precision control to reprogram cell profiles toward improved pro-regenerative environments. Acknowledgements: ERC CoG MagTendon No.772817; FCT Doctoral Grant SFRD/BD/144816/2019, and TERM. RES Hub (Norte-01-0145-FEDER-022190)

The application of immune regenerative strategies to deal with unsolved pathologies, such as tendinopathies, is getting attention in the field of tissue engineering exploiting the innate immunomodulatory potential of stem cells [1]. In this context, Amniotic Epithelial Cells (AECs) represent an innovative immune regenerative strategy due to their teno-inductive and immunomodulatory properties [2], and because of their high paracrine activity, become a potential stem cell source for a cell-free treatment to overcome the limitations of traditional cell-based therapies. Nevertheless, these immunomodulatory mechanisms on AECs are still not fully known to date. In these studies, we explored standardized protocols [3] to better comprehend the different phenotypic behavior between epithelial AECs (eAECs) and mesenchymal AECs (mAECs), and to further produce an enhanced immunomodulatory AECs-derived secretome by exposing cells to different stimuli. Hence, in order to fulfill these aims, eAECs and mAECs at third passage were silenced for CIITA and Nrf2, respectively, to understand the role of these molecules in an inflammatory response. Furthermore, AECs at first passage were seeded under normal or GO-coated coverslips to study the effect of GO on AECs, and further exposed to LPS and/or IL17 priming to increase the anti-inflammatory paracrine activity. The obtained results demonstrated how CIITA and Nrf2 control the immune response of eAECs and mAECs, respectively, under standard or immune-activated conditions (LPS priming). Additionally, GO exposition led to a faster activation of the Epithelial-Mesenchymal transition (EMT) through the TGFβ/SMAD signaling pathway with a change in the anti-inflammatory properties. Finally, the combinatory inflammatory stimuli of LPS+IL17 enhanced the paracrine activity and immunomodulatory properties of AECs. Therefore, AECs-derived secretome has emerged as a potential treatment option for inflammatory disorders such as tendinopathies. Acknowledgement: This research is part of the P4FIT project ESR1, funded under the H2020-ITN-EJD-Marie-Skłodowska-Curie grant agreement 955685

Tendinopathy is the most frequent musculoskeletal disease that requires medical attention. Mechanical overload has been considered as a key driver of its pathology. However, the underline mechanism on how overload induces tendinopathy and inflammation is unclear. Extracellular mitochondria (EM) are newly identified as cell-to-cell communicators. The aim of this study is to elucidate the role of mitochondria in overload-induced inflammation. We performed three-dimensional uniaxial stretching to mouse tendon organoid in bioreactors. Cyclic strain of uniaxial loadings included underload, normal load, and overload, according to previous work. We then harvested microvesicles including EM, from the bioreactor by differential centrifugation and evaluated their characteristics by flow cytometry and super-resolution confocal microscopy. Raw 264.7 mouse macrophage cell line was used for chemotaxis assay in a Boyden Chamber System with Magnetic-Activated Cell Sorting Technology. EM induced cytokines secretion by macrophages was analyzed by a bead-based multiplex assay panel. N-Acetyl-L-cysteine (NAC) was used as the antioxidant to tendon organoid to regulate mitochondrial fitness. We showed mechanical load induced tendon organoid to release microvesicles including mitochondria. The size of microvesicles is mainly in the range from 220nm to 880nm. More than 75% of microvesicles could be stained by PKH26, confirming they were with lipophilic membrane. Super-resolution confocal microscopy identified two forms of mitochondria, including mitochondria encapsulated in vesicles and free mitochondria. Overload led to the degeneration of the organoid and induced microvesicles release containing most EM. Chemotaxis assay showed that EM from overloaded tendon organoid induced macrophages chemotaxis. In addition, microvesicles extracted from overloaded tendon organoid induced the production of proinflammatory cytokines including IL-6, KC (Keratinocyte-Derived Chemokine) and IL-18. NAC treatment to tendon cells could attenuate overload-induced macrophage chemotaxis. Overload induces EM releasing from tendon cells, which leads to chemotaxis of macrophages toward tendon, resulting in induction of inflammation

Interstitial supraspinatus tears can cause persistent subacromial impingement symptoms despite non operative treatment. Autologous tendon cell injection (ATI) is a non-surgical treatment for tendinopathies and tear. We report a randomised controlled study of ATI compared to corticosteroid injection (CS) as treatment for interstitial supraspinatus tears and tendinopathy. Inclusion criteria were patients with symptom duration > 6 months, MRI confirmed intrasubstance supraspinatus tear, and prior treatment with physiotherapy and ≥ one CS or PRP injection. Participants were randomised to receive ATI to the interstitial tear or corticosteroid injection to the subacromial bursa in a 2:1 ratio, under ultrasound guidance. Assessments of pain (VAS) and function (ASES) were performed at baseline, and 1, 3, 6 and 12 months post treatment. 30 participants (19 randomised to ATI) with a mean age of 50.5 years (10 females) and a mean duration of symptoms of 23.5 months. Baseline VAS pain and ASES scores were comparable between groups. While mean VAS pain scores improved in both groups at 3 months after treatment, pain scores were superior with ATI at 6 months (p=0.01). Mean ASES scores in the ATI group were superior to the CS group at 3 months (p=0.026) and 6 months (p=0.012). Seven participants in the CS group withdrew prior to 12 months due to lack of improvement. At 12 months, mean VAS pain in the ATI group was 1.6 ± 1.3. The improvements in mean ASES scores in the ATI group at 6 and 12 months were greater than the MCID (12.0 points). At 12 months, 95% of ATI participants had an ASES score > the PASS (patient acceptable symptom state). This is the first level one study using ATI to treat interstitial supraspinatus tear. ATI results in a significant reduction in pain and improvement in shoulder function

Relevant in vitro models emulating tendinopathies are highly needed to study these diseases and develop better treatments. We have recently proposed a new strategy that allows the automated 3D writing of microphysiological systems (MPS) embedded into its own biomimetic fibrillar support platform based on the self-assembling of cellulose nanocrystals (CNCs). Here, we explored this CNC platform for writing humanized in vitro tendon models using tendon decellularized extracellular matrix (dECM)-based bioinks to closely recapitulate the biophysical and biochemical cues of tendon cell niche and self-induce the tenogenic differentiation of stem cells. The proposed concept was further explored to study the crosstalk between the tendon core and vascular compartment. Porcine flexor tendons were decellularized to produce the dECM bioink hydrogel. hASCs were used as cell source and the bioink was directly printed within the CNC fluid gel. Tendon constructs were co-printed with compartmentalized microvascular structures to evaluate the cellular crosstalk with endothelial cells. The tendon-on-chip models showed high cell viability and proliferation during culture up to 21 days, and the synergy between dECM cues and printed patterns induced anisotropic cell organization similar to tendon tissues. Gene and protein analysis showed upregulation of the most important tendon related markers on tendon constructs, demonstrating that the biophysical and biochemical cues of dECM induced hASCs commitment toward tenogenic phenotype. In co-culture system, chemotaxis induced endothelial cells migration toward the tendon compartment, but without significant infiltration. Gene and protein expression results suggest that the cellular crosstalk established in this MPS with endothelial cells boosted hASCs tenogenesis, emulating tendon development stages. Overall, the proposed system might be promising for the automated fabrication of organotypic tendon-on-chip models that will be a valuable new tool to study tendon physiology, pathology, or the effect of drugs for the treatment of tendinopathy. Acknowledgments: EU H2020 for ERC-2017-CoG-772817; ERC-PoC-BioCHIPs-101069302; FCT/MCTES for 2022.05526.PTDC, 2020.03410.CEECIND, and PD/BD/129403/2017

Tendinopathy can commonly occur around the foot and ankle resulting in isolated rupture, debilitating pain and degenerative foot deformity. The pathophysiology and key cells involved are not fully understood. This is partly because the dense collagen matrix that surrounds relatively few resident cells limits the ability of previous techniques to identify and target those cells of interest. In this study, we apply novel single cell RNA sequencing (CITE-Seq) techniques to healthy and tendinopathic foot/ankle tendons. For the first time we have identified multiple sub-populations of cells in human tendons. These findings challenge the view that there is a single principal tendon cell type and open new avenues for further study. Healthy tendon samples were obtained from patients undergoing tendon transfer procedures; including tibialis posterior and FHL. Diseased tendon samples were obtained during debridement of intractable Achilles and peroneal tendinopathy, and during fusion of degenerative joints. Single cell RNA sequencing with surface proteomic analysis identified 10 sub-populations of human tendon derived cells. These included groups expressing genes associated with fibro-adipogenic progenitors (FAPs) as well as ITGA7+VCAM1- recently described in mouse muscle but, as yet, not human tendon. In addition we have identified previously unrecognised sub-classes of collagen type 1 associated tendon cells. Each sub-class expresses a different set of extra-cellular matrix genes suggesting they each play a unique role in maintaining the structural integrity of normal tendon. Diseased tendon harboured a greater proportion of macrophages and cytotoxic lymphocytes than healthy tendon. This inflammatory response is potentially driven by resident tendon fibroblasts which show increased expression of pro-inflammatory cytokines. Finally, identification of a previously unknown sub-population of cells found predominantly in tendinopathic tissue offers new insight into the underlying pathophysiology. Further work aims to identify novel proteins targets for possible therapeutic pathways

Shoulder injury related to vaccine administration (SIRVA) is a prolonged episode of shoulder dysfunction that commences within 24 to 48 hours of a vaccination. Symptoms include a combination of shoulder pain, stiffness, and weakness. There has been a recent rapid increase in reported cases of SIRVA within the literature, particularly in adults, and is likely related to the mass vaccination programmes associated with COVID-19 and influenza. The pathophysiology is not certain, but placement of the vaccination in the subdeltoid bursa or other pericapsular tissue has been suggested to result in an inflammatory capsular process. It has been hypothesized that this is associated with a vaccine injection site that is “too high” and predisposes to the development of SIRVA. Nerve conduction studies are routinely normal, but further imaging can reveal deep-deltoid collections, rotator cuff tendinopathy and tears, or subacromial subdeltoid bursitis. However, all of these are common findings within a general asymptomatic population. Medicolegal claims in the UK, based on an incorrect injection site, are unlikely to meet the legal threshold to determine liability. Cite this article: Bone Joint J 2023;105-B(8):839–842

This study of collegiate basketball players evaluated change over time (COT) in ultrasound shear wave (SW) elastography metrics across the basketball season, and correlated to morphologic changes on conventional ultrasound imaging, and VISA-P scores. In eleven male collegiate basketball players (mean age 19, age range 18–21), patella tendon (PT) ultrasound and SW elastography of both knees were performed at pre-season and post-season time points, and players reported their VISA-P scores throughout the season. Patella tendinopathy grade and SW metrics were correlated to VISA-P scores using Spearman correlation coefficients. Paired t-test was used to assess differences in mean SW metrics at pre-and post-season timepoints, accounting for leg dominance. 6 of 11 players (54.5%) had baseline patella tendinopathy on ultrasound progressing in 4 players. The mean change in VISA-P score was 15.18 (+/−8.55). No significant correlation was seen between ultrasound grades of tendinopathy and VISA-P. Pre-season SW velocities did not significantly correlate with baseline VISA-P scores. Post-season SW values and SW COT demonstrated strong correlation with change in VISA-P score in dominant and non-dominant knees. Although not statistically significant, there was a trend towards higher SW velocity for tendinopathy in both dominant and non-dominant knees at both study visits. SW metrics of the PT correlated to change in VISA-P scores in the dominant and non-dominant knees, whereas conventional ultrasound grades of patella tendinopathy did not. There was a trend towards higher SW velocities in patella tendinopathy which may indicate detection of change in intrinsic tissue stiffness

Tendons are characterised by an inferior healing capacity when compared to other tissues, ultimately resulting in the formation of a pathologically altered extracellular matrix structure. Although our understanding of the underlying causes for the development and progression of tendinopathies remains incomplete, mounting evidence indicates a coordinated interplay between tendon-resident cells and the ECM is critical. Our recent results demonstrate that the matricellular protein SPARC (Secreted protein acidic and rich in cysteine) is essential for regulating tendon tissue homeostasis and maturation by modulating the tissue mechanical properties and aiding in collagen fibrillogenesis [1,2]. Consequently, we speculate that SPARC may also be relevant for tendon healing. In a rat patellar tendon window defect model, we investigated whether the administration of recombinant SPARC protein can modulate tendon healing. Besides the increased mRNA expression of collagen type 1 and the downregulation of collagen type 3, a robust increase in the expression of pro-regenerative fibroblast markers in the repair tissue after a single treatment with rSPARC protein was observed. Additionally, pro-fibrotic markers were significantly decreased by the administration of rSPARC. Determination of structural characteristics was also assessed, indicating that the ECM structure can be improved by the application of rSPARC protein. Therefore, we believe that SPARC plays an important role for tendon healing and the application of recombinant SPARC to tendon defects has great potential to improve functional tendon repair

Aim. Our collaborative study aims to demonstrate that acute partial Achilles Tendon Tears (ATTs) are not separate diagnostic entities from full ATTs. and should be thought of as a continuum rather than binary partial or full. Methods. We pooled anonymised data from four hospitals, identifying patients with acute partial ATTs on USS reports from 2019–2021. Patients were only included if they had an acute injury and no previous background Achilles tendinopathy. Results. 91 patients had acute partial ATTs reported on USS. 74/91 (81%) of patients had clinical findings in keeping with a full ATT (positive Simmonds test, palpable gap). 88/91 (97%) of patients were managed according to local full ATT protocols. 2 patients had MRIs – one showed no tear, the other showed a full rupture. 2 patients underwent surgical repair and both intra-operatively were found to have full ATTs. Conclusion. Our regional data suggests that a significant proportion (81%) of USS diagnosed partial ATTs may in fact be misdiagnosed full ATTs. All injuries clinically suspicious for an ATT should be managed according to local Achilles Protocol. USS is useful to diagnose the presence or absence of a tear but is not good at differentiating partial vs full tear. There is significant tendon end fibrillation and overlap on USS of an acute full ATT, which can give the impression of a partial ATT. More research is needed into whether any threshold exists to support the current distinction of “partial” and “full” as relates to management and outcomes

Traumatic acute or chronic tendon injuries are a wide clinical problem in modern society, resulting in important economic burden to the health system and poor quality of life in patients. Due to the low cellularity and vascularity of tendon tissue the repair process is slow and inefficient, resulting in mechanically, structurally, and functionally inferior tissue. Tissue engineering and regenerative medicine are promising alternatives to the natural healing process for tendon repair, especially in the reconstruction of large damaged tissues. The aim of TRITONE project is to develop a smart, bioactive implantable 3D printed scaffold, able to reproduce the structural and functional properties of human tendon, using FDA approved materials and starting from MSC and their precursor, MPC cell mixtures from human donors. Total cohort selected in the last 12 months was divided in group 1 (N=20) of subjects with tendon injury and group 2 (N=20) of healthy subject. Groups were profiled and age and gender matched. Inclusion criteria were age>18 years and presence of informed consent. Ongoing pregnancy, antihypertensive treatment, cardiovascular diseases, ongoing treatment with anti-aggregants, acetylsalicylic-acid or lithium and age<18 years were exclusion criteria. Firstly, we defined clinical, biological, nutritional life style and genetic profile of the cohort. The deficiency of certain nutrients and sex hormonal differences were correlated with tendon-injured patients. It was established the optimal amount of MPC/MSC human cell (collected from different patients during femoral neck osteotomy). Finally, most suitable biomaterials for tendon regeneration and polymer tendon-like structure were identified. Hyaluronic acid, chemical surface and soft-molecular imprinting (SOFT-MI) was used to functionalize the scaffold. These preliminary results are promising. It will be necessary to enroll many more patients to identify genetic status connected with the onset of tendinopathy. The functional and structural characterization of smart bioactive tendon in dynamic environment will represent the next project step

The purpose of this study was to evaluate the beneficial effects of r-Irisin (IR) on human primary tenocytes (hTCs) in vitro. Indeed, Irisin is secreted from muscles in response to exercise and mediates many beneficial effects on tissues and organs. Tissue samples (n=3) were analyzed by histology and immunohistochemistry for αVβ5 receptor. hTCs isolated, culture expanded were treated with: 1) RPMI medium as control; 2) IR at different concentrations; 3) IL-1β; 4) pre-treated with IL-1β for 24 h and then co-treated with IR; 5) pre-treated with IR for 24 h and then co-treated with IL-1β. We evaluated: cell metabolic activity (MTT); cell proliferation (trypan blue staining and PicoGreen); nitrite concentration (Griess). The analysis were performed in triplicate for each donor and each experiment was repeated at least three times. Data were expressed as mean ± S.D. One-way ANOVA analysis was used to compare the groups under exam. We found the presence of the αVβ5 receptor on hTCs plasma membrane supporting the potential interaction with irisin. Cell proliferation was significantly increased with IR at 5, 10 and 25 ng/mL. IR 25 ng/mL after IL1β pre-treatment was able to counteract the increase of nitrite production (p < 0.001) compared to the inflamed hTCs (p < 0.01; p < 0.0001), as well as IR at 10 and 25 ng/ml showed a protective role from oxidative damage. We observed a significant increase in cell metabolic viability in culture under IR at 5 and 25 ng/mL (p < 0.001; p < 0.05) in the pre-treated IR groups, whereas IR showed anti-inflammatory effects at the highest concentration of r-Irisin (p < 0.05). This is the first study reporting the capability of irisin to attenuate tendinopathy in vitro by acting on acute inflamed tenocytes. Our results confirmed and highlighted the potential cross-talk mechanism between muscle and tendon

Tendinopathy is a tendon pathology often resulting from a failed healing response to tendon injury. Activated protein C (APC) is a natural anti-coagulant with anti-inflammatory and wound healing promoting functions, which are mainly mediated by its receptors, endothelial protein C receptor (EPCR) and protease activated receptors (PARs). This study aimed to determine whether APC stimulates tenocyte healing and if so, to assess the involvement of the receptors. Mouse-tail tenocytes were isolated from 3-week-old wild type (WT), PAR- 1 knockout (KO) and PAR-2 KO mice. The expression of EPCR, PAR-1 and −2 and the effect of APC on tenocytes tendon healing and the underlying mechanisms were investigated by Reverse transcription real time PCR, western blot, 3- (4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay, zymography, and scratch wound healing/ migration assay. When compared to WT cells, PAR-1 KO tenocytes showed increased cell proliferation (3.3-fold, p<0.0001), migration (2.7-fold, p<0.0001) and wound healing (3-fold, p<0.0001), whereas PAR-2 KO cells displayed decreased cell proliferation (0.6-fold, p<0.05) and no change in cell migration or wound healing. APC at 1 μg/ml stimulated WT and PAR-1 KO tenocyte proliferation (~1.3, respectively, p<0.05) and wound healing (~1.3-fold, respectively, p<0.05), and additionally promoted PAR1-KO cell migration (1.4-fold, p<0.0001). APC only increased the migration (2-fold, p<0.05) of PAR-2 KO tenocytes. The activation of AKT, extracellular signal-regulated kinase (ERK)-2, and glycogen synthase kinase (GSK)-β3, the intracellular molecules that are associated with cell survival/growth, and matrix metalloproteinase (MMP)-2 that is related to cell migration and wound healing, were increased in all three cell lines in response to APC treatment. These findings show that PAR-1 and PAR-2 act differentially in tenocyte proliferation/migration/wound healing. APC likely promotes tenocyte proliferation/ wound healing via PAR-2, not PAR-1

Chronic Achilles tendinopathy is characterised by sub-acute inflammation with pro-inflammatory type 1 macrophages (M1), tissue degeneration and consequent partial or total tendon injury. Control of the inflammatory response and M1-to-M2 macrophage polarisation can favour tendon healing both directly and indirectly, by allowing for the regenerative process driven by local mesenchymal stem cells. Ten patients (3 females and 7 males aged between 32 and 71 years old) with partial Achilles tendon injury were treated with injections of autologous peripheral blood mononuclear cells (PB-MNCs). The cell concentrate was obtained from 100-120 cc of each patient's blood with a selective point-of-care filtration system. PB-MNCs remained trapped in the filter and were injected immediately after sampling. Around 60% of the PB-MNC concentrate was injected directly into the injured area, while the remaining 40% was injected in smaller amounts into the surrounding parts of the Achilles tendon affected by tendinosis. All patients were evaluated both clinically with the help of the American Orthopaedic Foot & Ankle Society (AOFAS) scale, and radiologically (MRI examination) at baseline and 2 months after the PB-MNC injection. A clinical reassessment with the AOFAS scale was also performed 6 months after the intervention. The rehabilitation protocol implied full weight-bearing walking immediately after the procedure, light physical activity 3-4 days after the injection, and physiotherapist-assisted stretching exercises and eccentric training. In all patients, functional and radiological signs of tendon healing processes were detected as early as 2 months after a single treatment and the AOFAS scale rose from the initial mean value of 37.5 (baseline) to 85.4 (6 months). Our preliminary results indicate that regenerative therapies with PB-MNCs can prove useful for partial Achilles tendon injuries as a valid alternative to surgical options, especially when other conservative approaches have failed. Advantages of this therapy include rapid execution, no need for an operating theatre, easy reproducibility, quick recovery and good tolerability regardless of the patient's age (the procedure is not to be performed in subjects who are below 18 years old). Further studies on the topic are recommended to confirm these observations

Background. Previous studies have individually shown extracorporeal shockwave therapy (ESWT) to be beneficial for mid-substance Achilles tendinopathy, insertional Achilles tendinopathy or plantar fasciitis. The purpose of this pragmatic study was to determine the efficacy of ESWT in managing the three main causes of refractory heel pain in our routine clinical practice. Methods. 236 patients (261 feet) aged between 25 – 81 years (mean age 50.4) were treated in our NHS institute with ESWT between April 2014 and May 2016. They all underwent a clinical and radiological assessment (ultrasonography +/− magnetic resonance imaging) to determine the primary cause of heel pain. Patients were subsequently categorized into three groups, mid-substance Achilles tendinopathy (55 cases), insertional Achilles tendinopathy (55 cases) or plantar fasciitis (151 cases). If their symptoms were recalcitrant to compliant first line management for 6 months, they were prescribed three consecutive ESWT sessions at weekly intervals. All outcome measures (foot & ankle pain score, EQ-5D) were recorded at baseline and 3-month follow-up (mean 18.3 weeks, range 11.4 to 41). Results. Complete data sets were obtained for 41% of the ESWT treatments (107/261). EQ-5D scores showed a statistically significant improvement between baseline and follow-up in all three-treatment groups; mid-substance Achilles tendinopathy 0.681 to 0.734, insertional Achilles tendinopathy 0.687 to 0.742 and plantar fasciitis 0.684 to 0.731 (p< 0.05). The foot & ankle pain scores grouped for all causes of heel pain also showed a statistically significant reduction from 6.78 at baseline to 5.36 at follow-up (p< 0.05). Conclusion. Overall our results showed that ESWT is an effective tool for the management of all refractory heel pain in an NHS foot & ankle clinical practice

Tendon diseases are prevalent health concerns for which current therapies present limited success, in part due to the intrinsically low regenerative ability of tendons. Therefore, tissue engineering presents a potential to improve this outcome. Here, we hypothesize that a concurrent control over both biophysical and biochemical stimuli will boost the tenogenic commitment of stem cells, thus promoting regeneration. To achieve this, we combine molecularly imprinted nanoparticles (MINPs), which act as artificial amplifiers for endogenous growth factor (GF) activity, with bioinspired anisotropic hydrogels. 2. to manufacture 3D tenogenic constructs. MINPs were solid phase-imprinted using a TGF-β3 epitope as template and their affinity for the target was assessed by SPR and dot blot. Magnetically-responsive microfibers were produced by cryosectioning electrospun meshes containing iron oxide nanoparticles. The constructs were prepared by encapsulating adipose tissue-derived stem cells (ASCs), microfibers, and MINPs within gelatin hydrogels, while aligning the microfibers with an external magnetostatic field during gelation. This allows an effective modulation of hydrogel fibrillar topography, mimicking the native tissue's anisotropic architecture. Cell responses were analyzed by multiplex immunoassay, quantitative polymerase chain reaction, and immunocytochemistry. MINPs showed an affinity for the template comparable to monoclonal antibodies. Encapsulated ASCs acquired an elongated shape and predominant orientation along the alignment direction. Cellular studies revealed that combining MINPs with aligned microfibers increased TGF-β signaling via non-canonical Akt/ERK pathways and upregulated tendon-associated gene expression, contrasting with randomly oriented gels. Immunostaining of tendon-related proteins presented analogous outcomes, corroborating our hypothesis. Our results thus demonstrate that microstructural cues and biological signals synergistically direct stem cell fate commitment, suggesting that this strategy holds potential for improving tendon healing and might be adaptable for other biological tissues. The proposed concept highlights the GF-sequestering ability of MINPs which allows a cost-effective alternative to recombinant GF supplementation, potentially decreasing the translational costs of tissue engineering strategies. Acknowledgements: The authors acknowledge the funding from the European Union's Horizon 2020 under grant No. 772817; from FCT/MCTES for scholarships PD/BD/143039/2018 & COVID/BD/153025/2022 (S.P.B.T.), and PD/BD/129403/2017 (S.M.B.), co-financed by POCH and NORTE 2020, under the Portugal 2020 partnership agreement through the European Social Fund, for contract 2020.03410.CEECIND (R.M.A.D.) and project 2022.05526.PTDC; and from Xunta de Galicia for grant ED481B2019/025 (A.P.)