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  • 1. Abat, F
    et al.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Alfredson Tendon Clinic Inc, Umeå, Sweden; Pure Sports Medicine Clinic, ISEH, UCLH, London, UK.
    Cucchiarini, M
    Madry, H
    Marmotti, A
    Mouton, C
    Oliveira, J M
    Pereira, H
    Peretti, G M
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Stephen, J
    van Bergen, C J A
    de Girolamo, L
    Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part II2018In: Journal of experimental orthopaedics, ISSN 2197-1153, Vol. 5, no 38Article in journal (Refereed)
    Abstract [en]

    The treatment of painful chronic tendinopathy is challenging. Multiple non-invasive and tendon-invasive methods are used. When traditional non-invasive treatments fail, the injections of platelet-rich plasma autologous blood or cortisone have become increasingly favored. However, there is little scientific evidence from human studies supporting injection treatment. As the last resort, intra- or peritendinous open or endoscopic surgery are employed even though these also show varying results. This ESSKA basic science committee current concepts review follows the first part on the biology, biomechanics and anatomy of tendinopathies, to provide a comprehensive overview of the latest treatment options for tendinopathy as reported in the literature.

  • 2.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. ISEH, UCLH, London, UK; Pure Sports Medicine Clinic, London, UK.
    Masci, Lorenzo
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Surgical plantaris tendon removal for patients with plantaris tendon-related pain only and a normal Achilles tendon: a case series2018In: BMJ Open Sport & Exercise Medicine, ISSN 2055-7647, Vol. 4, no 1, article id e000462Article in journal (Refereed)
    Abstract [en]

    Objectives: Surgical removal of the plantaris tendon can cure plantaris-associated Achilles tendinopathy, a condition in which Achilles and plantaris tendinopathy coexist. However, rare cases with plantaris tendinopathy alone are often misdiagnosed due to a normal Achilles tendon.

    Design and setting: Prospective case series study at one centre.

    Participants: Ten consecutive patients (9 men and one woman, mean age 35 years, range 19–67) with plantaris tendon-related pain alone in altogether 13 tendons were included. All had had a long duration (median 10 months, range 3 months to 10 years) of pain symptoms on the medial side of the Achilles tendon mid-portion. Preoperative ultrasound showed thickened plantaris tendon but a normal Achilles tendon.

    Interventions: Operative treatment consisting of ultrasound-guided excision of the plantaris tendon.

    Primary and secondary outcome measures: Scores from Victorian Institute of Sports Assessment-Achilles questionnaire (VISA-A)were taken preoperatively and postoperatively (median duration 10 months). Patient satisfaction and time until full return to sports activity level was asked by a questionnaire.

    Results: The VISA-A scores increased from 61 (range 45–81) preoperatively to 97 (range 94–100) postoperatively (p<0.01). Follow-up results at 10 months (range 7–72 months) on 9/10 patients showed full satisfaction and return to their preinjury sports or recreational activity

    Conclusion: The plantaris tendon should be kept in mind when evaluating painful conditions in the Achilles tendon region, especially when no Achilles tendinopathy is present. Excision of the plantaris tendon via a minor surgical procedure in local anaesthesia results in a good outcome.

  • 3.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. ISEH, UCLH, London, UK; Pure Sports Medicine Clinic, London, UK.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Dr Alfen, Orthopedic Spine Center, 97080 Würzburg, Germany.
    Clinical presentation and surgical management of chronic Achilles tendon disorders: a retrospective observation on a set of consecutive patients being operated by the same orthopedic surgeon2018In: Foot and Ankle Surgery, ISSN 1268-7731, E-ISSN 1460-9584, Vol. 24, no 6, p. 490-494Article in journal (Refereed)
    Abstract [en]

    Background: Non-invasive treatment is not always successful in patients with Achilles tendon disorders, and surgical treatment is instituted as the next step. There is sparse knowledge about the diagnoses, pain levels before surgery, surgically confirmed pathologies and postoperative complications in large patient groups.

    Aims: To study the diagnoses, pain scores before surgery, macroscopic surgical findings and postoperative complications in a series of patients treated for Achilles disorders.

    Material and methods: One surgeon operated on 771 Achilles tendons of 481 men and 290 women during a 10-year period. The clinically and ultrasound confirmed diagnoses, pre-operative pain and functional scores (Visual Analogue Scale, VAS, range 0-100; Victorian Institute Sports Tendon Assessment - Achilles questionnaire, VISA-A), macroscopic findings during surgery and postoperative complications, were retrospectively collected from a database.

    Results: Clinically, by ultrasound and during surgery midportion Achilles tendinopathy was confirmed in 519 (67%) patients, 41% of them had a thickened plantaris tendon located close the Achilles tendon. Partial midportion rupture was found in 31 (4%) patients, chronic midportion rupture in 12 (2%) patients and insertional Achilles tendinopathy, including superficial and retro-calcaneal bursitis, Haglund deformity, distal Achilles tendinopathy, plantaris tendon pathology, and bone spurs, in 209 (27%) patients. The mean pre-operative pain scores for midportion Achilles tendinopathy were 73 (VAS) and 45 (VISA-A), and for insertional Achilles tendinopathy 77 (VAS) and 39 (VISA-A). For midportion Achilles tendinopathy there were 14 (3%), and for insertional Achilles tendinopathy 10 (5%), postoperative complications.

    Conclusions: Patients presenting high pain scores from midportion Achilles tendinopathy were the most common. Plantaris tendon involvement is a frequent observation. For insertional Achilles tendinopathy the combination of pathology in the subcutaneous and retrocalcaneal bursa, a Haglund deformity and distal Achilles tendinopathy/tendinosis was most frequent. 

  • 4.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bilateral Achilles tendinosis: the similar morphological appearance and the benefit of unilateral treatment has benefits for the contralateral tendon2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A18-A18Article in journal (Other academic)
  • 5.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unilateral surgical treatment for patients with midportion Achilles tendinopathy may result in bilateral recovery2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 19, p. 1421-1424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bilateral midportion Achilles tendinopathy/tendinosis is not unusual, and treatment of both sides is often carried out. Experiments in animals suggest of the potential involvement of central neuronal mechanisms in Achilles tendinosis. OBJECTIVES: To evaluate the outcome of surgery for Achilles tendinopathy. METHODS: This observational study included 13 patients (7 men and 6 women, mean age 53 years) with a long duration (6-120 months) of chronic painful bilateral midportion Achilles tendinopathy. The most painful side at the time for investigation was selected to be operated on first. Treatment was ultrasound-guided and Doppler-guided scraping procedure outside the ventral part of the tendon under local anaesthetic. The patients started walking on the first day after surgery. Follow-ups were conducted and the primary outcome was pain by visual analogue scale. In an additional part of the study, specimens from Achilles and plantaris tendons in three patients with bilateral Achilles tendinosis were examined. RESULTS: Short-term follow-ups showed postoperative improvement on the non-operated side as well as the operated side in 11 of 13 patients. Final follow-up after 37 (mean) months showed significant pain relief and patient satisfaction on both sides for these 11 patients. In 2 of 13 patients operation on the other, initially non-operated side, was instituted due to persisting pain. Morphologically, it was found that there were similar morphological effects, and immunohistochemical patterns of enzyme involved in signal substance production, bilaterally. CONCLUSION: Unilateral treatment with a scraping operation can have benefits contralaterally; the clinical implication is that unilateral surgery may be a logical first treatment in cases of bilateral Achilles tendinopathy.

  • 6.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    In mid-portion Achilles tendinosis the plantaris tendon shows the same tendinosis-like morphological features and expression of the non-neuronal cholinergic system as the Achilles tendon itself2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A3-A3Article in journal (Other academic)
  • 7. Masci, Lorenzo
    et al.
    Alfredson, Hakan
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Plantaris tendon and association with mid-portion Achilles tendinopathy: Is the plantaris tendon a contributing factor in mid-portion Achilles tendinopathy?2019In: Apunts. Medicina de l'Esport, ISSN 1886-6581, Vol. 54, no 201, p. 13-18Article in journal (Refereed)
    Abstract [en]

    Plantaris tendon is implicated in some cases of load-resistant Achilles tendinopathy. The tendon courses close to the medial Achilles tendon mid-portion prior to insertion onto Mid-portion Achilles the medial calcaneus, although there is variation in course and insertion. Clinical suspicion of tendinopathy plantaris involvement includes persistent medial Achilles pain unresponsive to a rehabilitation programme and imaging revealing a thickened plantaris tendon and/or focal medial Achilles tendinosis. Potential mechanisms include compression or shearing forces between the plantaris and Achilles tendons. Initial treatment should consist of a modified loading programme avoiding end-range loading. Resistant cases may be amenable to surgical excision of the plantaris demonstrating good clinical outcomes in the short and tong term, although the evidence is limited to case series. Percutaneous methods show promise but require further evaluation.

  • 8. Masci, Lorenzo
    et al.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    van Schie, Hans T M
    Alfredson, Håkan
    Achilles tendinopathy - do plantaris tendon removal and Achilles tendon scraping improve tendon structure?: A prospective study using ultrasound tissue characterisation2015In: BMJ Open Sport & Exercise Medicine, ISSN 2055-7647, Vol. 1, no 1, article id e000005Article in journal (Refereed)
    Abstract [en]

    Objectives The plantaris tendon has recently been described as a possible important factor in midportion Achilles tendinopathy. Ultrasound tissue characterisation (UTC) is a method to study tendon structure (matrix integrity). The effect of plantaris tendon removal on Achilles tendon structure was studied using UTC.

    Design and setting Prospective case series study at one centre.

    Participants Nine tendons in eight physically active and healthy patients (mean age 39 years) with chronic painful midportion Achilles tendinopathy were included. Preoperative two-dimensional ultrasound and UTC showed midportion Achilles tendinopathy (tendinosis) with medial tendon changes and suspected plantaris tendon involvement. Patients with previous operations to the Achilles tendon were excluded.

    Interventions Operative treatment consisted of excision of the plantaris tendon and scraping of the ventromedial surface of the Achilles tendon under a local anaesthetic.

    Primary and secondary outcome measures UTC examination and clinical scoring with the VISA-A questionnaire were performed preoperatively and 6 months postoperatively.

    Results At 6 months follow-up, UTC demonstrated a statistically significant (t=5.40, p<0.001) increase in the mean organised matrix (echo-type I+II) and a decrease in the mean disorganised matrix (echo-type III+IV). Seven out of eight patients were satisfied, and the VISA-A score had increased significantly (p<0.001) from 56.8 (range 34–73) preoperatively to 93.3 (range 87–100) postoperatively.

    Conclusions Excision of the plantaris tendon and scraping of the ventromedial Achilles tendon in chronic midportion tendinopathy seem to have the potential to improve tendon structure and reduce tendon pain. Studies on a larger group of patients and with a longer follow-up period are needed.

  • 9.
    Ruergård, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Dr. Alfen Orthopaedic Spine Center, Würzburg, Germany.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Institute of Sport, Exercise and Health (ISEH), University College London Hospitals (UCLH), London, UK; Pure Sports Medicine Clinic, London, UK.
    Results of minimally invasive Achilles tendon scraping and plantaris tendon removal in patients with chronic midportion Achilles tendinopathy: A longer-term follow-up study2019In: Safety, ISSN 0036-3375, E-ISSN 2050-3121, Vol. 7, article id UNSP 2050312118822642Article in journal (Refereed)
    Abstract [en]

    Background: Treatment with ultrasound and colour Doppler–guided minimally invasive Achilles tendon scraping and plantaris tendon removal has shown promising short-term results in patients with chronic painful midportion Achilles tendinopathy.

    Methods: In a follow-up study, 182 consecutive patients (241 tendons) who had undergone Achilles tendon scraping and plantaris tendon removal were contacted on telephone by an independent investigator. The patients who answered the telephone call were included, and they answered a questionnaire on telephone and then also sent their written answers. The questionnaire included information about patient satisfaction with the result of the treatment, time to return to full Achilles tendon loading activity, and a pain score (Visual Analogue Scale-VAS).

    Results: The follow-up period was 5.8 years (mean) (range of 2–13 years) after surgery. Altogether, 110 patients (136 Achilles tendons), 52 years (mean)(range 18-73) old at surgery could be reached and were included. In total, 81 tendons were operated with the Achilles scraping procedure alone, and for 55 Achilles operations also a plantaris tendon removal was performed. For 93% of the operated tendons, the patients were satisfied with the surgical outcome and the VAS had decreased from 74 preoperatively to 8 postoperatively. Nine male patients (9 tendons), five operated with scraping + plantaris removal, had remaining tendon pain during loading and were not satisfied. Their VAS score ranged from 22 to 91. For 21% of the operated tendons, some occasional mild discomfort not preventing from full tendon loading, was reported. There were no differences in pain reduction and satisfaction rates between men and women, and between Achilles scraping alone and scraping plus plantaris removal.

    Conclusion: Ultrasound and colour Doppler–guided surgical Achilles tendon scraping and plantaris tendon removal in patients with chronic painful midportion Achilles tendinopathy show remaining good clinical outcomes and high satisfaction rates in this longer-term follow-up.

  • 10.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The plantaris tendon in relation to the Achilles tendon in midportion Achilles tendinopathy: studies on morphology, innervation and signalling substances2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Midportion Achilles tendinopathy (tendinosis) is a troublesome painful condition, often characterised by pain, local swelling, tenderness and functional disability. Despite extensive research, the pathogenesis is poorly understood and treatment remains challenging. Features related to the peritendinous connective tissue can be of importance. Recently it has been suggested that the plantaris tendon might be involved in this condition. Furthermore, it has been hypothesised that tendon pain and the tendinosis-related tissue changes in tendinopathy might be mediated by signalling substances such as glutamate and acetylcholine. A clinical observation, not scientifically evaluated, has been that unilateral treatment for bilateral Achilles tendinosis can lead to an effect on the contralateral side.

         The aim of this work was to examine the morphology and innervation patterns in the plantaris tendon and the peritendinous connective tissue in between the Achillles and plantaris tendons in midportion Achilles tendinopathy, and to evaluate if plantaris tendon removal has an effect on Achilles tendon structure. Another aim was to determine if unilateral treatment for Achilles tendinopathy targeting the peritendinous connective tissue can result in bilateral recovery. Furthermore the presence of non-neuronal cholinergic and glutamate systems was examined.

         Sections of plantaris tendons with adjacent peritendinous connective tissue from patients with midportion Achilles tendinopathy were stained for morphology (H&E), and innervation patterns were evaluated using antibodies against general nerve marker (PGP9.5), sensory (CGRP) and sympathetic (TH) nerve fibres and Schwann cells (S-100β). Furthermore immunostainings against non-neuronal aceylcholine (ChAT) and glutamate signalling components (glutamate, VGluT2, NMDAR1) were performed. Plantaris tendon cells were cultured and also stained for glutamate signalling components, and were stimulated with glutamate and glutamate receptor agonist NMDA. Furthermore, Ultrasound Tissue Characterisation (UTC) was used to monitor the integrity of the Achilles tendon collagen structure after plantaris tendon removal.

         Plantaris tendons exhibited tendinosis-like tissue patterns such as hypercellularity, collagen disorganisation and large numbers of blood vessels. The peritendinous connective tissue between the plantaris and Achilles tendons contained large numbers of fibroblasts and blood vessels and to some extent macrophages and mast cells. A marked innervation was found in the peritendinous connective tissue and there were also nerve fibres in the loose connective tissue spaces within the tendon tissue proper. Most nerve fibres were identified as sensory fibres. Some nerve fascicles in the peritendinous connective tissue showed absence of axons but homogenous reactions for Schwann cell marker. Tenocytes and cells in the peritendinous connective tissue expressed ChAT, glutamate, VGluT2 and NMDAR1. Tendon cells in vitro expressed VGluT2, NMDAR1 and glutamate. UTC showed significant improvement of Achilles tendon integrity 6 months after surgical plantaris tendon removal and scraping procedure. Eleven out of thirteen patients reported of a bilateral recovery after unilateral surgical treatment.

         The results of this work show that plantaris tendons exhibit tendinosis-like tissue changes, internal innervation and features that suggest occurrence of glutamate and acetylcholine production and signalling. Plantaris removal improves Achilles tendon structure suggesting possible compressive/shearing interference between the Achilles and plantaris tendons in tendinopathy. The peritendinous connective tissue shows marked innervation, which thus might transmit pain when being compressed. The partial absence of axons indicates a possible nerve degeneration. On the whole, the study gives new evidence favouring that the plantaris tendon and the peritendinous connective tissue might be of importance for pain and the tendinopathy process in midportion Achilles tendinopathy.

  • 11.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. 2Dr. Alfen, Orthopaedic Spine Center, Wuerzburg, Germany.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. ISEH, University College London Hospitals, UK; Pure Sports Medicine Clinic, London, UK.
    Richly innervated soft tissues covering the superficial aspect of the extensor origin in patients with chronic painful tennis elbow - Implication for treatment?2017In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 17, no 2, p. 97-103Article in journal (Refereed)
    Abstract [en]

    Background: Tennis elbow is difficult to treat. The results of surgical treatments are not convincing. Treatment studies on Achilles and patellar tendinopathy targeting the richly innervated and vascularized soft tissues outside the tendon have shown promising outcomes. The innervation patterns in the fibrous/fatty tissues superficially to the elbow extensor origin have not been clarified.

    Methods: Nine tissue specimens from the fibrous/fatty tissue covering the extensor origin was taken from seven patients (mean age: 45 years) undergoing surgical treatment for chronic painful tennis elbow. The specimens were stained for morphology (haematoxylin & eosin, H&E) and immunohistochemically for general nerve marker protein gene product 9.5 (PGP 9.5) and markers for sympathetic (tyrosine hydroxylase, TH) and sensory nerve fibres (calcitonin gene-related peptide, CGRP).

    Results: All specimens contained multiple blood vessels and nerve structures indicated by morphology and immunoreactions. There was a frequent occurrence of TH reactions, especially peri-vascularly, but also in nerve fascicles. Immunoreactions for CGRP were seen in nerve fascicles and isolated nerve fibres.

    Conclusion: The results provide new information on the innervation patterns of the superficial tissues of the extensor origin and their potential as source of tennis elbow pain. Level of Evidence: IV.

  • 12.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Pure Sports Med Clin, Cabot Pl West, London E14 4QS, England and Univ Coll London Hosp, Inst Sports Exercise & Hlth, 170 Tottenham Court Rd, London W1T 7HA, England.
    Docking, S. I.
    Masci, L.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    The plantaris tendon: a narrative review focusing on anatomical features and clinical importance2016In: The Bone & Joint Journal, ISSN 2049-4394, E-ISSN 2049-4408, Vol. 98B, no 10, p. 1312-1319Article, review/survey (Refereed)
    Abstract [en]

    In recent years, the plantaris tendon has been implicated in the development of chronic painful mid-portion Achilles tendinopathy. In some cases, a thickened plantaris tendon is closely associated with the Achilles tendon, and surgical excision of the plantaris tendon has been reported to be curative in patients who have not derived benefit following conservative treatment and surgical interventions. The aim of this review is to outline the basic aspects of, and the recent research findings, related to the plantaris tendon, covering anatomical and clinical studies including those dealing with histology, imaging and treatment.

  • 13.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Ferguson, Mark
    Centre for Sports Medicine and Orthopaedics, Rosebank Johannesburg.
    Roos, Beverley
    Centre for Sports Medicine and Orthopaedics, Rosebank Johannesburg.
    Bagge, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The plantaris tendon in association with mid-portion Achilles tendinosis: tendinosis-like morphological features and presence of a non-neuronal cholinergic system2013In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 28, p. 623-632Article in journal (Refereed)
    Abstract [en]

    The plantaris tendon is often neglected in morphological/clinical studies on the lower extremity. There is, however, clinical evidence that the plantaris tendon is involved in cases with Achilles midportion tendinopathy/tendinosis. It is nevertheless unclear if the plantaris tendon exhibits tendinosis-like features in this situation. We therefore investigated the plantaris tendon of patients with midportion Achilles tendinosis when the plantaris tendon was found to be located very close to or invaginated into the Achilles tendon, a situation which very often has been found to be the case. There was a very large number of tenocytes in the tendon tissue and the tenocytes showed abnormal and irregular appearances, exhibiting widened/rounded and wavy appearances, and were frequently lined up in rows. These features are characteristic features in Achilles tendinosis tendons. The tendon cells showed a distinct immunoreaction for the acetylcholine (ACh) -producing enzyme choline acetyltransferase (ChAT). Frequent fibroblasts were found in the loose connective tissue and these cells also showed a marked ChAT immunoreaction. The study shows that the plantaris tendon is morphologically affected in a similar way to the Achilles tendon in cases with midportion Achilles tendinosis and medial pain. The plantaris tendon may accordingly be a co-factor in these cases. The results also favour that there is a local ACh production both within the tendon tissue of the plantaris tendon and in the loose connective tissue. In conclusion, it is evident that plantaris tendons lying invaginated into or very close to the Achilles tendon in cases with midportion Achilles tendinosis show similar tendinosis features, as previously shown for the Achilles tendon itself in these cases.

  • 14.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Achilles tendinopathy is a troublesome sports-related condition involving blood vessel ingrowth into the tendon tissue: Studies on the adjacent plantaris tendon and the peritendinous connective tissue suggest that TNF-alpha can be highly involved in the vascular and tissue changes2013In: Proceedings of the International Congress on Sports Science Research and Technology Support / [ed] Jan Cabri, Pedro Pezarat Correia, João Barreiros, SciTePress, 2013, Vol. 1, p. 45-50Conference paper (Other academic)
    Abstract [en]

    Achilles tendinopathy/tendinosis is a troublesome condition which is frequently occurring in response to sports related activities. It can lead to an ending of the sport activity. There is evidence which shows that ingrowth of blood vessels occurs from the peritendinous tissue. In well-established treatments the areas of these vessels are targeted. In Achilles tendinosis there is frequently a coalescing of the plantaris tendon with the Achilles tendon. TNF-alpha is known to be involved in blood vessel remodelling events and angiogenesis. With these facts as background, the peritendinous connective tissue located inbetween the plantaris and Achilles tendons and the plantaris tendon itself in cases with Achilles tendinosis were evaluated concerning expression of TNF-alpha and TNF receptor II (TNFRII). It was found that there were expressions of TNF-alpha in the numerous cells located in the peritendinous connective tissue and that the very frequently occurring blood vessels located in t his tissue as well as in the tendon tissue exhibited marked TNFRII reactions. The tenocytes were shown to exhibit moderate TNF-alpha reactions and very strong TNFRII reactions. The observations suggest that TNF-alpha is highly involved in the blood vessel remodelling in tendinosis and that TNF-alpha also is involved in tenocyte function.

  • 15.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, L
    LeRoux, S
    Forsgren, S
    Danielson, P
    Plantaris tendon tissue of tendinosis patients displays a glutamate signallingmachinery that may influence tenocyte phenotypeManuscript (preprint) (Other academic)
  • 16.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Le Roux, Sandrine
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Chen, Jialin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Glutamate signaling through the NMDA receptor reduces the expression of scleraxis in plantaris tendon derived cells2017In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 18, article id 218Article in journal (Refereed)
    Abstract [en]

    Background: A body of evidence demonstrating changes to the glutaminergic system in tendinopathy has recently emerged. This hypothesis was further tested by studying the effects of glutamate on the tenocyte phenotype, and the impact of loading and exposure to glucocorticoids on the glutamate signaling machinery.

    Methods: Plantaris tendon tissue and cultured plantaris tendon derived cells were immunohisto-/cytochemically stained for glutamate, N-Methyl-D-Aspartate receptor 1 (NMDAR1) and vesicular glutamate transporter 2 (VGluT2). Primary cells were exposed to glutamate or receptor agonist NMDA. Cell death/viability was measured via LDH/MTS assays, and Western blot for cleaved caspase 3 (c-caspase 3) and cleaved poly (ADP-ribose) polymerase (c-PARP). Scleraxis mRNA (Scx)/protein(SCX) were analyzed by qPCR and Western blot, respectively. A FlexCell system was used to apply cyclic strain. The effect of glucocorticoids was studies by adding dexamethasone (Dex). The mRNA of the glutamate synthesizing enzymes Got1 and Gls, and NMDAR1 protein were measured. Levels of free glutamate were determined by a colorimetric assay.

    Results: Immunoreactions for glutamate, VGluT2, and NMDAR1 were found in tenocytes and peritendinous cells in tissue sections and in cultured cells. Cell death was induced by high concentrations of glutamate but not by NMDA. Scleraxis mRNA/protein was down-regulated in response to NMDA/glutamate stimulation. Cyclic strain increased, and Dex decreased, Gls and Got1 mRNA expression. Free glutamate levels were lower after Dex exposure.

    Conclusions: In conclusion, NMDA receptor stimulation leads to a reduction of scleraxis expression that may be involved in a change of phenotype in tendon cells. Glutamate synthesis is increased in tendon cells in response to strain and decreased by glucocorticoid stimulation. This implies that locally produced glutamate could be involved in the tissue changes observed in tendinopathy.

  • 17.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Dr Alfen Orthopedic Spine Center, 97080 Würzburg, Germany.
    Chen, Jialin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The tenocyte phenotype of human primary tendon cells in vitro is reduced by glucocorticoids2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, article id 467Article in journal (Refereed)
    Abstract [en]

    Background: The use of corticosteroids (e.g., dexamethasone) as treatment for tendinopathy has recently been questioned as higher risks for ruptures have been observed clinically. In vitro studies have reported that dexamethasone exposed tendon cells, tenocytes, show reduced cell viability and collagen production. Little is known about the effect of dexamethasone on the characteristics of tenocytes. Furthermore, there are uncertainties about the existence of apoptosis and if the reduction of collagen affects all collagen subtypes.

    Methods: We evaluated these aspects by exposing primary tendon cells to dexamethasone (Dex) in concentrations ranging from 1 to 1000 nM. Gene expression of the specific tenocyte markers scleraxis (Scx) and tenomodulin (Tnmd) and markers for other mesenchymal lineages, such as bone (AlplOcn), cartilage (AcanSox9) and fat (CebpαPparg) was measured via qPCR. Cell viability and proliferation was calculated using a MTS Assay. Cell death was measured by LDH assay and cleaved caspase-3 using Western Blot. Gene expression of collagen subtypes Col1Col3 and Col14 was analyzed using qPCR.

    Results: Stimulation with Dex decreased cell viability and LDH levels. Dex also induced a significant reduction of Scx gene expression and a marked loss of fibroblast like cell shape. The mRNA for all examined collagen subtypes was found to be down-regulated. Among non-tendinous genes only Pparg was significantly increased, whereas AcanAlpl and Sox9 were reduced.

    Conclusions: These results indicate a Dex induced phenotype drift of the tenocytes by reducing scleraxis expression. Reduction of several collagen subtypes, but not cell death, seems to be a feature of Dex induced tissue degeneration.

  • 18.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Choline acetyltransferase and the nicotinic acetylcholine receptor AChR alpha 7 in experimental myositis2015In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 29, no 1, p. 189-194Article in journal (Refereed)
    Abstract [en]

    It is not known to what extent a non-neuronal cholinergic system is involved in myositis (muscle inflammation) evoked by marked muscle overuse. Therefore, in the present study, a recently established rabbit myositis model was used and the expression patterns of ChAT and nicotinic acetylcholine receptor AChR alpha 7 (alpha 7nAChR) were evaluated. Immunohistochemistry and in situ hybridization were used. The model leads to myositis including occurrence of muscle fiber necrosis. It was found that the infiltrating white blood cells as well the walls of small blood vessels exhibited immunoreactivity for both ChAT and alpha 7nAChR There was also pronounced immunoreactivity for these in the white blood cells that had coalesced within the necrotic muscle fibers. The findings show that there is a presence of a non-neuronal cholinergic system in the situation of muscle inflammation. Cholinergic effects may be highly involved in the inflammation-modifying events that occur in muscle overuse.

  • 19.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Harandi, Vahid M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredsson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Pure Sports Medicine Clinic, London, UK; ISEH, UCLH, London, UK.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy2015In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 15, no 2, p. 197-206Article in journal (Refereed)
    Abstract [en]

    Objectives: The plantaris tendon is increasingly recognised as an important factor in midportion Achilles tendinopathy. Its innervation pattern is completely unknown. Methods: Plantaris tendons (n=56) and associated peritendinous tissue from 46 patients with midportion Achilles tendinopathy and where the plantaris tendon was closely related to the Achilles tendon were evaluated. Morphological evaluations and stainings for nerve markers [general (PGP9.5), sensory (CGRP), sympathetic (TH)], glutamate NMDA receptor and Schwann cells (S-100β) were made. Results: A marked innervation, as evidenced by evaluation for PGP9.5 reactions, occurred in the peritendinous tissue located between the plantaris and Achilles tendons. It contained sensory and to some extent sympathetic and NMDAR1-positive axons. There was also an innervation in the zones of connective tissue within the plantaris tendons. Interestingly, some of the nerve fascicles showed a partial lack of axonal reactions. Conclusion: New information on the innervation patterns for the plantaris tendon in situations with midportion Achilles tendinopathy has here been obtained. The peritendinous tissue was found to be markedly innervated and there was also innervation within the plantaris tendon. Furthermore, axonal degeneration is likely to occur. Both features should be further taken into account when considering the relationship between the nervous system and tendinopathy

  • 20.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Dr. Alfen Orthopaedic Spine Center, Würzburg, Germany.
    Renström, Lina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Pure Sports Medicine Clinic, London, UK ; ISEH, UCLH, London, UK.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Marked expression of TNF receptors in human peritendinous tissues including in nerve fascicles with axonal damage: Studies on tendinopathy and tennis elbow2017In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 17, no 3, p. 226-236Article in journal (Refereed)
    Abstract [en]

    Background: The peritendinous connective tissues can have importance in chronic tendon pain. Recently cytokine TNF-alpha has been suggested to be involved in tendinopathic processes. It is not known how TNF-alpha and its receptors TNFR1 and TNFR2 are expressed in peritendinous tissues.

    Methods: The objective for this study was to immunohistochemically evaluate the expression patterns of these in the peritendinous tissue located between the plantaris and Achilles tendons and the one located superficially to the extensor origin at the elbow region for patients with tendinopathy/tennis elbow.

    Results: The nerve fascicles were of two types, one type being homogenously stained for the nerve markers beta III-tubulin and neurofilament and the other showing deficits for these suggesting features of axonal damage. Much more distinct TNFR1/TNFR2 immunoreactions were seen for the latter nerve fascicles. TNFR1 was seen in axons, TNFR2 mainly in Schwann cells. TNFR1 and particularly TNFR2 were seen in walls of parts of blood vessels. The dispersed cells showed frequently TNFR1 and TNFR2 immunoreactivity.

    Discussion: These findings suggest that TNF-alpha can be related to degenerative events but also attempts for healing concerning the nerve structures. The marked expression of the TNF-alpha system in the peritendinous tissue suggests an impact of TNF-alpha in tendinopathy/tennis elbow.

  • 21.
    Spang, Christoph
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    University of British Columbia, Vancouver Coastal Health and Research Institute.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    VGluT2 and NMDAR1 expression in cells in the inflammatory infiltrates in experimentally induced myositis: evidence of local glutamate signaling suggests autocrine/paracrine effects in an overuse injury model2012In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 35, no 1, p. 39-48Article in journal (Refereed)
    Abstract [en]

    It is not known whether a glutamate signaling system is involved in muscle inflammation (myositis). In the present study, we examined this question in the soleus muscle in a laboratory model of myositis resulting from repetitive overuse induced by electrical stimulation and injection of pro-inflammatory substances. Sections of rabbit soleus muscle with an induced myositis, i.e., exhibiting infiltration of inflammatory cells, were examined immunohistochemically using antibodies against vesicular glutamate transporter VGluT2 and the glutamate receptor NMDAR1. In situ hybridization for demonstration of VGluT2 mRNA was also performed. Specific reactions for both VGluT2 and NMDAR1 could be observed immunohistochemically in the same cells. In situ hybridization demonstrated the occurrence of VGluT2 mRNA in the cells. Double staining showed that the VGluT2 reactions were detectable in cells marked with T cell/neutrophil marker and in cells expressing eosinophil peroxidase. These data suggest the occurrence of previously unknown glutamate-mediated autocrine/paracrine effects within the inflammatory infiltrates during the development of muscle inflammation.

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