Medicine:Tendinosis

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Tendinosis

Tendinosis means and is sometimes called chronic tendinitis, chronic tendinopathy, or chronic tendon injury. It is damage to a tendon at a cellular level (the suffix "osis" implies a pathology of chronic degeneration without inflammation). It is thought to be caused by microtears in the connective tissue in and around the tendon, leading to an increase in tendon repair cells. This may lead to reduced tensile strength, thus increasing the chance of tendon rupture. Tendinosis is often misdiagnosed as tendinitis because of the limited understanding of tendinopathies by the medical community.[1] Classic characteristics of "tendinosis" include degenerative changes in the collagenous matrix, hypercellularity, hypervascularity, and a lack of inflammatory cells which has challenged the original misnomer "tendinitis".[2][3]

Causes

Tendinosis of the common extensor tendon of the elbow (“tennis elbow”), as of the Rotator Cuff, is a common cause of pain in the elbow or shoulder.[4] The general opinion is that tendinosis is due to tendon overuse, and failed healing of the tendon.[5] In addition, the extensor carpi radialis brevis muscle plays a key role.[6]

Pathophysiology

Histological findings include granulation tissue, microrupture, degenerative changes, and there is no traditional inflammation. As a consequence, “lateral elbow tendinopathy or tendinosis” is used instead of “lateral epicondylitis”.[7]

Examination of tennis elbow tissue reveals noninflammatory tissue, so the term “angiofibroblastic tendinosis” is used.[8]

Cultures from tendinopathic tendons contain an increased production of type III collagen.[9][10]

Longitudinal sonogram of the lateral elbow displays thickening and heterogeneity of the common extensor tendon that is consistent with tendinosis, as the ultrasound reveals calcifications, intrasubstance tears, and marked irregularity of the lateral epicondyle. Although the term “epicondylitis” is frequently used to describe this disorder, most histopathologic findings of studies have displayed no evidence of an acute, or a chronic inflammatory process. Histologic studies have demonstrated that this condition is the result of tendon degeneration, which causes normal tissue to be replaced by a disorganized arrangement of collagen. Therefore, the disorder is more appropriately referred to as “tendinosis” or “tendinopathy” rather than “tendinitis.”[11]

Colour Doppler ultrasound reveals structural tendon changes, with vascularity and hypo-echoic areas that correspond to the areas of pain in the extensor origin.[12]

Load-induced non-rupture tendinopathy in humans is associated with an increase in the ratio of collagen III:I proteins, a shift from large to small diameter collagen fibrils, buckling of the collagen fascicles in the tendon extracellular matrix, and buckling of the tenocyte cells and their nuclei.[13]

Diagnosis

Symptoms can vary from an ache or pain and stiffness to the local area of the tendon, or a burning that surrounds the whole joint around the affected tendon. With this condition, the pain is usually worse during and after activity, and the tendon and joint area can become stiffer the following day as swelling impinges on the movement of the tendon. Many patients report stressful situations in their life in correlation with the beginnings of pain, which may contribute to the symptoms.

Swelling in a region of micro damage or partial tear may be detected visually or by touch.

Medical imaging

Ultrasound imaging can be used to evaluate tissue strain, as well as other mechanical properties.[14]

Ultrasound-based techniques are becoming more popular because of its affordability, safety, and speed. Ultrasound can be used for imaging tissues, and the sound waves can also provide information about the mechanical state of the tissue.[15]

Increased water content and disorganized collagen matrix in tendon lesions may be detected by ultrasonography or magnetic resonance imaging.

Treatment

An injured tendon is very slow to heal. Partial tears heal by the rapid production of disorganized type-III collagen which is weaker than normal tendon.[citation needed] Recurrence of injury in the damaged region of the tendon is common.

Rehabilitation, rest, and gradual return to the activity in which tendinosis was experienced is a common therapy. There is evidence to suggest that tendinosis is not an inflammatory disorder; anti-inflammatory drugs are not an effective treatment;[16] and inflammation is not the cause of this type of tendon dysfunction.[17] There is a variety of treatment options but more research is necessary to determine their effectiveness. Initial recovery is usually within 2 to 3 months, and full recovery usually within 3 to 6 months. About 80% of patients will fully recover within 12 months.[18] If the conservative therapy doesn't work, then surgery can be an option. This surgery consists of the excision of abnormal tissue. Time required to recover from surgery is about 4 to 6 months.[19] Studies with a rat model of fatigue-damaged tendons suggested that delaying exercise until after the initial inflammatory stage of repair could promote remodelling more rapidly.[20]

Research

Eccentric loading and extracorporeal shockwave therapy are currently being researched as possible treatments for tendinosis. One study found the two modalities to be equally effective in treating tendinosis of the Achilles tendon and more effective than a 'wait and see' approach.[21] Other treatments for which research is on-going include vitamin E, vitamin B6, nitric oxide, Platelet Rich Plasma (PRP),[22] and stem cell injections.

Vitamin C

One study found increased Achilles tendon healing in rats supplemented with high doses of vitamin C, which is needed for collagen synthesis.[23]

Vitamin E

Vitamin E has been found to increase the activity of fibroblasts, leading to increased collagen fibrils and synthesis, which seems to speed up the regeneration and increase the regenerative capacity of tendons.[24][25]

Nitric oxide

Nitric oxide (NO) also appears to play a role in tendon healing[26] and inhibition of its synthesis impairs tendon healing.[27] The use of a nitric oxide delivery system (glyceryl trinitrate patches) applied over the area of maximal tenderness was tested in three clinical trials for the treatment of tendinopathies and was found to significantly reduce pain and increase range of motion and strength.[28]

One study found that arginine supplementation, which may possibly increase NO signaling,[29] was able to increase the speed of tendon healing[30]

Soft tissue mobilization

Augmented Soft Tissue Mobilization (ASTM) is a form of manual therapy that has been shown in studies on rats to speed the healing of tendons by increasing fibroblast activity.[31][32] One case study showed ASTM resulting in full recovery in the case of an athlete suffering from chronic ankle pain and fibrosis, after an unsuccessful course of surgery and conventional physical therapy.[33]

Eccentric loading

A promising line of therapy involves eccentric loading exercises involving lengthening muscular contractions.[34]

Inflatable brace

The use of an inflatable brace (AirHeel) was shown to be as effective as eccentric loading in the treatment of chronic Achilles tendinopathy. Both modalities produced significant reduction in pain scores, but their combination was no more effective than either treatment alone.[35]

Shock-wave therapy

Shock-wave therapy (SWT) may be effective in treating calcific tendinosis in both humans[36] and rats.[37] In rat subjects, SWT increased levels of healing hormones and proteins leading to increased cell proliferation and tissue regeneration in tendons. Another study found no evidence that SWT was useful in treating chronic pain in the Achilles tendon.[38]

Tendon bioengineering

The future of non-surgical care for tendinosis is likely bioengineering. Ligament reconstruction is possible using mesenchymal stem cells and a silk scaffold.[39] These same stem cells were capable of seeding repair of damaged animal tendons.[40] Autologous tenocyte implantation is currently being tested for tendinosis. There is a large randomized, double-blind, placebo controlled trial being conducted in the Netherlands to test the safety and efficacy of tenocyte therapy. Results from the trial are expected by April 2013.

Autologous tenocyte injection

A study investigated autologous tenocyte injection for the treatment of severe, chronic resistant lateral epicondylitis. A needle biopsy was used on the patellar tendon, and the extracted tendon cells were expanded by in vitro culture. The autologous tenocytes were sorted and purified by real-time polymerase chain reaction, and amplified by flow cytometry. The tenocytes were then injected into the injured tendinopathy site, which was the origin of the extensor carpi radialis brevis tendon, under the guidance of an ultrasound. After the autologous tenocyte injection treatment, patients with chronic lateral epicondylitis showed improved clinical function and structural repair at the origin of the common extensor tendon.[41]

Nonbulbar dermal sheath cells

RepliCel has planned a Phase 1/2 Achilles tendinosis clinical trial using fibroblasts that are isolated from the nonbulbar dermal sheath cells of a hair follicle, and is recruiting in Q1 2015. The tendon treatment will be tested in approximately 28 subjects. Nonbulbar dermal sheath cells are used because they produce more type I collagen than fibroblasts that are derived from adipose tissue. Type I collagen is the primary collagen in tendons. Nonbulbar dermal sheath cells will be replicated, and then reintroduced into the wounded tendons with ultrasound. After the injections, subjects will be assessed for pain, safety, and function, as well as changes in interstitial tears, tendon thickness, echotexture, and neovascularity.[42][43]

Injections of microRNA

Scientists found that mir-29a, a single microRNA, through its interaction with a protein, interleukin 33, plays a key role in regulating the production of collagens in tendon disease. Loss of miR29a from human tendons results in an increase in collagen type-3 production, which is a key feature of tendon disease. The replacement of miR-29a in the damaged tendon cells in the laboratory restores collagen production to pre injury levels. A trial will put injections of microRNA – small molecules that help regulate gene expression – into the tendon to decrease the production of type 3 collagen and switch to type-1.[44]

Allogenic adipose-derived mesenchymal stem cells

As of November 2013, researchers at the Seoul National University Hospital will be looking to recruit participants into a clinical trial to evaluate the efficacy of allogenic adipose-derived mesenchymal stem cells (ALLO-ASC) for the treatment of a lateral epicondylitis tendon injury where the duration of the symptoms is over six months. Adipose-derived mesenchymal stem cells will be administrated to the patients with lateral epicondylitis (tennis elbow) by an ultrasonographic-guided injection.[45]

Elastography ultrasound

Researchers have tried to analyze tissue strain and mechanical properties using elastography, which is an acoustical imaging technique that measures strain distributions in tissues that result from stress or compression of the tissue. Strain is inversely related to stiffness, so under a given amount of stress, tissue that displays less strain is assumed to be stiffer than tissue that exhibits more strain. Elastography is therefore an indirect method to estimate tissue stiffness.[14]

One limitation of elastography is that it is inherently linear when ultrasound wave velocity and the material properties do not change during the strain measurement. This is a problem in soft tissues like tendons, as they are nonlinear in stiffness, and can undergo large deformations in activity. Elastography measures strain, and to more completely described the mechanical behavior, more data, like stiffness or stress would be required.[14]

Acoustoelastography ultrasound

Acoustoelastic theory is based on the principle that the acoustic properties of a material are altered as the material is loaded and deformed. The properties can be measured as a change in amplitude and wave velocity.[15]

With the use of A-mode ultrasound, researchers have derived an acoustic relationship between reflected wave amplitude, and strain-dependent stiffness and stress in a deformed material.[15]

As tendon tension increases, the intensity of reflected ultrasonic echoes increases. The increased intensity results in a brighter B-mode ultrasound image.[14]

Acoustoelastography is an ultrasound technique that relates ultrasonic wave amplitude changes to the mechanical properties of a tendon.[46]

It is an ultrasound-based model that can be used evaluate tendon function. Gradual deformations of a tendon can produce cine loops, where changes in echo intensity can be observed. By analyzing the echo intensity changes with Acoustoelastography, one can deduce the stiffness gradient, which is the rate of change of normalised stiffness as a function of strain.[47]

EchoSoft ultrasound software from the Wisconsin Alumni Research Foundation and Echometrix applies the theory of acoustoelasticity to measure musculoskeletal (tendon and ligament) tissue. The software examines previously unused information found by ultrasound waves to quantify the extent of musculoskeletal injuries, or a patient's progress in a healing process.[48]

Ultrasonic Percutaneous Tenotomy

Percutaneous ultrasonic tenotomy provided continued pain relief and functional improvement for recalcitrant tennis elbow at a 3-year follow-up.[49]

Other animals

Bowed tendon is a horseman's term for tendinitis (inflammation) and tendinosis (degeneration), most commonly seen in the superficial digital flexor tendon in the front leg of horses.

Diagnosis

When the superficial digital flexor tendon of horses is damaged, there is a thickening of the tendon, giving it a bowed appearance when the leg is viewed from the side.

Medical imaging

A study tested the repeatability and feasibility of using acoustoelastography for in vivo measurement of stiffness gradients in the superficial digital flexor tendons (SDFTs) of clinically normal horses. The results show that acoustoelastography is a repeatable and feasible technique for measuring stiffness gradients of superficial digital flexor tendons in clinically normal horses, and acoustoelastography has the potential to be used for comparing diseased and healthy tendon states.[50]

A report describes the use of acoustoelastography to monitor the mechanical healing of an Achilles tendon laceration in a dog after suture repair. Serial acoustoelastography examinations of the tendon showed that mechanical properties improved throughout the recovery period. At 29 weeks, the mechanical properties of the repaired tendon were similar to that of the normal contralateral Achilles mechanism.[46]

A study shows that acoustoelastography is a repeatable and feasible method for measuring stiffness gradients in equine superficial digital flexor tendons.[47]

The acoustoelastic strain gauge is an ultrasound-based tissue evaluation technique that relates echo intensity changes that are observed during the stretching or relaxation tendons to the mechanical properties of the tissue. The method deduces stiffness gradient (the rate of change of normalized stiffness as a function of tissue strain) by evaluating the ultrasound dynamic images that are captured from tissue as it gradually deforms. Acoustoelastic strain gauge has been shown to accurately model stiffness and strain within tendons in vitro. To determine the repeatability and feasibility of in vivo ASG measurements of canine tendon function, stiffness gradients for the gastrocnemius tendons of dogs were recorded. Findings indicate that acoustoelastic strain gauge is a repeatable and feasible technique for measuring stiffness gradients in canine tendons.[51]

Pathophysiology

Achilles tendons in rats were studied with acoustoelastography ultrasound. After a tendon injury, and during tendon healing, vascularity changes and cellular activity are vital to the formation of granular tissue in the tendon gap, and the subsequent development of neo-tendinous tissue that replaces damaged native tissue. Normal, intact tendon is composed mainly of type I collagen, and type III collagen increases after injury. Another study has recorded an association between collagen fibers and echogenicity tendon during Achilles tendon healing.[52]

This report further indicates that a decrease in type I procollagen (and increase in type III collagen and periostin) correlates to reduced strength, echo intensity, and normalized stiffness. It shows that tissue normalized stiffness is linearly correlated to procollagen I, while echo intensity is seen to be nonlinearly correlated to type I procollagen. Furthermore, the increase in M1 macrophages, blood vessels, and proliferating cells that occur within two weeks of the injury are associated with a formation of granulation tissue. Ultimate stress, echo intensity, and normalized stiffness are all their lowest during these times. The results assert that the reduction in stress and normalized stiffness that is measured by ultrasonic and mechanical methods correlate well with the biological aspect of tendon healing.[52]

Treatment

Mesenchymal stem cells, derived from a horse's bone marrow or fat, are currently being used for tendon repair in horses. [53]

Confusion between tendonitis and tendinosis[54]

Tendonitis is a very common, but misleading term. By definition, the suffix "-itis" means "inflammation of". Inflammation[55] is the body's local response to tissue damage which involves red blood cells, white blood cells, blood proteins with dilation of blood vessels around the site of injury. Tendons are relatively avascular.[56][54] Corticosteroids are drugs that reduce inflammation. Corticosteroids can be useful to relieve chronic tendinopathy pain, improve function, and reduce swelling in the short term. However, there is a greater risk of long-term recurrence.[57] They are typically injected along with a small amount of a numbing drug called lidocaine. Research shows that tendons are weaker following corticosteroid injections. Tendinitis is still a very common diagnosis, though research increasingly documents that what is thought to be tendinitis is usually tendinosis.[58]

See also


References

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  4. ↑ Mohamadi, Amin; Chan, Jimmy J.; Claessen, Femke M. A. P.; Ring, David; Chen, Neal C. (January 2017). "Corticosteroid Injections Give Small and Transient Pain Relief in Rotator Cuff Tendinosis: A Meta-analysis". Clinical Orthopaedics and Related Research 475 (1): 232–243. doi:10.1007/s11999-016-5002-1. ISSN 1528-1132. PMID 27469590. 
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  7. ↑ du Toit, C; Stieler, M; Saunders, R; Bisset, L; Vicenzino, B (2008). "Diagnostic accuracy of power Doppler ultrasound in patients with chronic tennis elbow". British Journal of Sports Medicine 42 (11): 572–576. doi:10.1136/bjsm.2007.043901. ISSN 0306-3674. 
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  9. ↑ "Tenocytes from ruptured and tendinopathic achilles tendons produce greater quantities of type III collagen than tenocytes from normal achilles tendons. An in vitro model of human tendon healing.". Am J Sports Med 28 (4): 499–505. 2000. doi:10.1177/03635465000280040901. PMID 10921640. 
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  12. ↑ Zeisig, Eva; Öhberg, Lars; Alfredson, Håkan (2006). "Sclerosing polidocanol injections in chronic painful tennis elbow-promising results in a pilot study". Knee Surgery, Sports Traumatology, Arthroscopy 14 (11): 1218–1224. doi:10.1007/s00167-006-0156-0. ISSN 0942-2056. 
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  14. ↑ 14.0 14.1 14.2 14.3 "Ultrasound echo is related to stress and strain in tendon". J Biomech 44 (3): 424–9. February 2011. doi:10.1016/j.jbiomech.2010.09.033. PMID 21030024. 
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  24. ↑ "Effects of "in situ" vitamin E on fibroblast differentiation and on collagen fibril development in the regenerating tendon". The International Journal of Developmental Biology (University Of The Basque Country Press) 1 (Supplemental): 181–2. 1996. PMID 9087752. 
  25. ↑ "Resorbable polyacrylic hydrogels derived from vitamin E and their application in the healing of tendons". Journal of Materials Science: Materials in Medicine (Kluwer Academic Publishers) 10 (10/11): 641–8. 1999. doi:10.1023/A:1008991825657. PMID 15347979. 
  26. ↑ Xia, W.; Szomor Z.; Wang Y.; Murrell G.A. (2006). "Nitric oxide enhances collagen synthesis in cultured human tendon cells". Journal of Orthopaedic Research (Wiley) 24 (2): 159–72. doi:10.1002/jor.20060. PMID 16435353. 
  27. ↑ Darmani, H.; Crossan J.C.; Curtis A. (2004). "Single dose of inducible nitric oxide synthase inhibitor induces prolonged inflammatory cell accumulation and fibrosis around injured tendon and synovium". Mediators of Inflammation (Hindawi Pub. Corp.) 13 (3): 157–64. doi:10.1080/09511920410001713556. PMID 15223606. 
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  29. ↑ Bailey; Winyard; Vanhatalo; Blackwell; DiMenna; Wilkerson; Jones (Nov 2010). "Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance". J Appl Physiol 109 (5): 1394–403. doi:10.1152/japplphysiol.00503.2010. PMID 20724562. 
  30. ↑ Moraes; Oliveira; Crespo-Lopez; Picanco-Diniz; Herculano (2013). "Local NO synthase inhibition produces histological and functional recovery in Achilles tendon of rats after tenotomy: tendon repair and local NOS inhibition.". Cell and Tissue Research 353 (3): 457–463. doi:10.1007/s00441-013-1662-2. 
  31. ↑ Craig J. Davidson et. al., "Rat tendon morphologic and functional changes resulting from soft tissue mobilization", Medicine & Science in Sports & Exercise, Mar. 1997, Vol. 29, No. 3, pp. 313-319.
  32. ↑ Gale M. Gehlsen, "Fibroblast responses to variation in soft tissue mobilization pressure", Medicine & Science in Sports & Exercise, Apr. 1999, Vol. 31, No. 4, pp. 531-535.
  33. ↑ Thomas J. Melham et. al., "Chronic ankle pain and fibrosis successfully treated with a new noninvasive augmented soft tissue mobilization technique (ASTM): a case report", Medicine & Science in Sports & Exercise, Jun. 1998, Vol. 30, No. 6, pp. 801-804.
  34. ↑ "Conservative management of midportion Achilles tendinopathy: a mixed methods study, integrating systematic review and clinical reasoning". Sports Med 42 (11): 941–67. November 2012. doi:10.2165/11635410-000000000-00000. PMID 23006143. 
  35. ↑ "Chronic Achilles Tendinopathy: A Prospective Randomized Study Comparing the Therapeutic Effect of Eccentric Training, the AirHeel Brace, and a Combination of Both". Am J Sports Med 35 (10): 1659–67. June 14, 2007. doi:10.1177/0363546507303558. PMID 17569792. 
  36. ↑ "Effectiveness of radial shock-wave therapy for calcific tendinosis of the shoulder: single-blind, randomized clinical study". Phys Ther 86 (5): 672–82. 2006. PMID 16649891. 
  37. ↑ "Extracorporeal shock waves promote healing of collagenase-induced Achilles tendinosis and increase TGF-beta1 and IGF-I expression". J Orthop Res 22 (4): 854–61. 2004. doi:10.1016/j.orthres.2003.10.013. PMID 15183445. 
  38. ↑ "Shock wave therapy for chronic Achilles tendon pain: a randomized placebo-controlled trial". Clin Orthop Relat Res 440: 199–204. 2005. doi:10.1097/01.blo.0000180451.03425.48. PMID 16239807. 
  39. ↑ "In vivo study of anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold". Biomaterials 29 (23): 3324–37. August 2008. doi:10.1016/j.biomaterials.2008.04.012. PMID 18462787. http://linkinghub.elsevier.com/retrieve/pii/S0142-9612(08)00244-5. 
  40. ↑ "[Repair of rabbit tendon by autologous bone marrow mesenchymal stem cells]" (in Chinese). Zhonghua Shao Shang Za Zhi 21 (3): 210–2. June 2005. PMID 15996290. 
  41. ↑ Wang, A.; Breidahl, W.; Mackie, K. E.; Lin, Z.; Qin, A.; Chen, J.; Zheng, M. H. (2013). "Autologous Tenocyte Injection for the Treatment of Severe, Chronic Resistant Lateral Epicondylitis: A Pilot Study". The American Journal of Sports Medicine 41 (12): 2925–2932. doi:10.1177/0363546513504285. ISSN 0363-5465. 
  42. ↑ Safety and Efficacy of RCT-01 in Men and Women With Unilateral, Chronic Achilles Tendinosis (ReaCT) In: ClinicalTrials.gov [Internet]. Last updated: March 12, 2015. Available from: https://clinicaltrials.gov/ct2/show/NCT02330146 NLM Identifier: NCT02330146.
  43. ↑ "Industry Update: Latest developments in stem cell research and regenerative medicine". Regenerative Medicine 8 (5): 535–542. 2013. doi:10.2217/rme.13.56. ISSN 1746-0751. 
  44. ↑ "MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease.". Nat Commun 6: 6774. 2015. doi:10.1038/ncomms7774. PMID 25857925. 
  45. ↑ Seoul National University Hospital. Treatment of Tendon Injury Using Mesenchymal Stem Cells (ALLO-ASC). In: ClinicalTrials.gov [Internet]. Last updated: November 22, 2013. Available from: http://clinicaltrials.gov/show/NCT01856140 NLM Identifier: NCT01856140.
  46. ↑ 46.0 46.1 Hans, E. C.; Sample, S. J.; Duenwald-Kuehl, S. E.; Vanderby, R.; Muir, P. (2014). "Use of acoustoelastography to evaluate tendon healing after surgical repair of an Achilles mechanism laceration and rehabilitation with a custom tarsal orthotic splint in a dog". Veterinary Record Case Reports 2 (1): e000046–e000046. doi:10.1136/vetreccr-2014-000046. ISSN 2052-6121. 
  47. ↑ 47.0 47.1 Brounts, S.H.; Ellison, M.E.; Duenwald-Kuehl, S.; Forrest, L.; Vanderby Jr, R. (2013). "In vivo Evaluation of Acoustoelastography in the Normal Equine Superficial Digital Flexor Tendon". Equine Veterinary Journal 45: 7–7. doi:10.1111/evj.12145_17. ISSN 0425-1644. 
  48. ↑ "September 2010 New Products". Journal of Orthopaedic & Sports Physical Therapy 40 (9): 598–601. 2010. doi:10.2519/jospt.2010.40.9.598. ISSN 0190-6011. 
  49. ↑ Seng, C.; Mohan, P. C.; Koh, S. B. J.; Howe, T. S.; Lim, Y. G.; Lee, B. P.; Morrey, B. F. (2015). "Ultrasonic Percutaneous Tenotomy for Recalcitrant Lateral Elbow Tendinopathy: Sustainability and Sonographic Progression at 3 Years". The American Journal of Sports Medicine 44 (2): 504–510. doi:10.1177/0363546515612758. ISSN 0363-5465. 
  50. ↑ "Reproducibility and feasibility of acoustoelastography in the superficial digital flexor tendons of clinically normal horses". Am. J. Vet. Res. 75 (6): 581–7. June 2014. doi:10.2460/ajvr.75.6.581. PMID 24866514. 
  51. ↑ "Feasibility and repeatability for in vivo measurements of stiffness gradients in the canine gastrocnemius tendon using an acoustoelastic strain gauge". Vet Radiol Ultrasound 54 (5): 548–54. 2013. doi:10.1111/vru.12052. PMID 23663072. 
  52. ↑ 52.0 52.1 "Temporal healing in rat achilles tendon: ultrasound correlations". Ann Biomed Eng 41 (3): 477–87. March 2013. doi:10.1007/s10439-012-0689-y. PMID 23149902. 
  53. ↑ "Current and future regenerative medicine - principles, concepts, and therapeutic use of stem cell therapy and tissue engineering in equine medicine.". Can Vet J 50 (2): 155–65. 2009. PMID 19412395. 
  54. ↑ 54.0 54.1 "tendinosis". The Free Dictionary. http://medical-dictionary.thefreedictionary.com/tendinosis. 
  55. ↑ "Inflammation". The Free Dictionary. http://medical-dictionary.thefreedictionary.com/Inflammation. 
  56. ↑ "avascular". The Free Dictionary. http://medical-dictionary.thefreedictionary.com/avascular. 
  57. ↑ Rees, J. D.; Stride, M.; Scott, A. (2013). "Tendons - time to revisit inflammation". British Journal of Sports Medicine 48 (21): 1553–1557. doi:10.1136/bjsports-2012-091957. ISSN 0306-3674. 
  58. ↑ Bass, Lmt (2012). "Tendinopathy: Why the Difference Between Tendinitis and Tendinosis Matters". International Journal of Therapeutic Massage & Bodywork: Research, Education, & Practice 5. doi:10.3822/ijtmb.v5i1.153. 

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