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1.  ggstThe role of tendon microcirculation in Achilles and patellar tendinopathy 
Tendinopathy is of distinct interest as it describes a painful tendon disease with local tenderness, swelling and pain associated with sonographic features such as hypoechogenic texture and diameter enlargement. Recent research elucidated microcirculatory changes in tendinopathy using laser Doppler flowmetry and spectrophotometry such as at the Achilles tendon, the patellar tendon as well as at the elbow and the wrist level. Tendon capillary blood flow is increased at the point of pain. Tendon oxygen saturation as well as tendon postcapillary venous filling pressures, determined non-invasively using combined Laser Doppler flowmetry and spectrophotometry, can quantify, in real-time, how tendon microcirculation changes over with pathology or in response to a given therapy. Tendon oxygen saturation can be increased by repetitive, intermittent short-term ice applications in Achilles tendons; this corresponds to 'ischemic preconditioning', a method used to train tissue to sustain ischemic damage. On the other hand, decreasing tendon oxygenation may reflect local acidosis and deteriorating tendon metabolism. Painful eccentric training, a common therapy for Achilles, patellar, supraspinatus and wrist tendinopathy decreases abnormal capillary tendon flow without compromising local tendon oxygenation. Combining an Achilles pneumatic wrap with eccentric training changes tendon microcirculation in a different way than does eccentric training alone; both approaches reduce pain in Achilles tendinopathy. The microcirculatory effects of measures such as extracorporeal shock wave therapy as well as topical nitroglycerine application are to be studied in tendinopathy as well as the critical question of dosage and maintenance. Interestingly it seems that injection therapy using color Doppler for targeting the area of neovascularisation yields to good clinical results with polidocanol sclerosing therapy, but also with a combination of epinephrine and lidocaine.
doi:10.1186/1749-799X-3-18
PMCID: PMC2397381  PMID: 18447938
2.  Combined intra-tendinous injection of Platelet Rich Plasma and bevacizumab accelerates and improves healing compared to Platelet Rich Plasma in tendinosis: comprehensive assessment on a rat model 
Summary
Purpose:
the aim of our study was to assess the potential of combined intratendinous injection of an anti-angiogenic drug: bevacizumab (AA) and Platelet Rich Plasma (PRP) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity.
Material and method:
twenty rats (80 patellar and Achilles tendons) were used for the study. We induced tendinosis (T+) in 80 tendons (patellar=40 and Achilles=40) by injecting under ultrasonography (US) guidance Collagenase 1® (day 0 = D0). Clinical examination was performed at D3, immediately followed by either PRP and AA (AAPRPT+, n=40) or PRP (PRPT+ n=40, control) US-guided intratendinous injection. Follow-up at D6, D18 and D25 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA+PRP toxicity, we looked for necrosis or rupture on the 40 AAPRPT+.
Results:
all AAPRPT+ showed better joint mobilization compared to PRPT+ at D6 (p=0.03), D18 (p=0.04) and D25 (p=0.02). Similar results were found regarding US and histology, with smaller collagen fiber diameters (D6, p≤0.017, D25, p≤0.015), less disorganization and fewer neovessels (D25, p=0.004) in AAPRPT+ compared to PRPT+. No AA+PRP local toxicity was discovered in histology assessment.
Conclusion:
our study suggests that combined injection of AA and PRP in tendinosis accelerates and improves tendon’s healing compared PRP used alone, with no local toxicity.
PMCID: PMC4241427  PMID: 25489554
anti-angiogenic; PRP; rat; tendon; tendinosis; US
3.  Eccentric training as a new approach for rotator cuff tendinopathy: Review and perspectives 
World Journal of Orthopedics  2014;5(5):634-644.
Excessive mechanical loading is considered the major cause of rotator cuff tendinopathy. Although tendon problems are very common, they are not always easy to treat. Eccentric training has been proposed as an effective conservative treatment for the Achilles and patellar tendinopathies, but less evidence exists about its effectiveness for the rotator cuff tendinopathy. The mechanotransduction process associated with an adequate dose of mechanical load might explain the beneficial results of applying the eccentric training to the tendons. An adequate load increases healing and an inadequate (over or underuse) load can deteriorate the tendon structure. Different eccentric training protocols have been used in the few studies conducted for people with rotator cuff tendinopathy. Further, the effects of the eccentric training for rotator cuff tendinopathy were only evaluated on pain, function and strength. Future studies should assess the effects of the eccentric training also on shoulder kinematics and muscle activity. Individualization of the exercise prescription, comprehension and motivation of the patients, and the establishment of specific goals, practice and efforts should all be considered when prescribing the eccentric training. In conclusion, eccentric training should be used aiming improvement of the tendon degeneration, but more evidence is necessary to establish the adequate dose-response and to determine long-term follow-up effects.
doi:10.5312/wjo.v5.i5.634
PMCID: PMC4133471  PMID: 25405092
Cellular; Mechanotransduction; Rehabilitation; Shoulder Impingement; Supraspinatus; Tendon injuries
4.  Increased expression of IL-6 family members in tendon pathology 
Rheumatology (Oxford, England)  2012;51(7):1161-1165.
Objectives. Histological examination of pathological tendon generally does not reveal signs of inflammation. However, the inflammatory cytokine IL-6 has been shown to be expressed in ruptured rotator cuff tendon. The aim of this study was to investigate the expression of IL-6 family members in painful posterior tibialis tendon (PTT) and in painful and ruptured Achilles tendon (AT) compared with normal tendon.
Methods. AT samples were obtained from cadavers (normal) or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. PTT samples were obtained from patients undergoing surgery for other reasons (normal) and from patients with PTT dysfunction (painful). Total RNA was extracted and mRNA expression was analysed by quantitative real-time PCR.
Results. Collagen type I α-chain I (COL1A1) expression was increased in both painful PTT and AT compared with normal. Ciliary neurotrophic factor levels were increased in painful PTT only. In the painful AT, cyclooxygenase-2 (COX2) and IL-6 expression increased compared with normal. In the ruptured AT, levels of VEGF A, COX2, oncostatin-M, leukaemia inhibitory factor and IL-6 expression were higher compared with both normal and painful AT. IL-6R expression decreased in both painful and ruptured AT compared with normal.
Conclusion. Painful AT and PTT show different expression patterns, indicating a substantial difference between those two tendinopathies. Inflammatory markers are up-regulated in painful and particularly in ruptured AT, pointing towards a role of inflammation not only in rupture healing, but also in Achilles tendinopathy.
doi:10.1093/rheumatology/kes002
PMCID: PMC3380247  PMID: 22337942
gene expression; tendinopathy; tendon rupture; OSM; LIF; CNTF; IL-6; Achilles tendon; posterior tibialis tendon
5.  Deciphering the pathogenesis of tendinopathy: a three-stages process 
Our understanding of the pathogenesis of "tendinopathy" is based on fragmented evidences like pieces of a jigsaw puzzle. We propose a "failed healing theory" to knit these fragments together, which can explain previous observations. We also propose that albeit "overuse injury" and other insidious "micro trauma" may well be primary triggers of the process, "tendinopathy" is not an "overuse injury" per se. The typical clinical, histological and biochemical presentation relates to a localized chronic pain condition which may lead to tendon rupture, the latter attributed to mechanical weakness. Characterization of pathological "tendinotic" tissues revealed coexistence of collagenolytic injuries and an active healing process, focal hypervascularity and tissue metaplasia. These observations suggest a failed healing process as response to a triggering injury. The pathogenesis of tendinopathy can be described as a three stage process: injury, failed healing and clinical presentation. It is likely that some of these "initial injuries" heal well and we speculate that predisposing intrinsic or extrinsic factors may be involved. The injury stage involves a progressive collagenolytic tendon injury. The failed healing stage mainly refers to prolonged activation and failed resolution of the normal healing process. Finally, the matrix disturbances, increased focal vascularity and abnormal cytokine profiles contribute to the clinical presentations of chronic tendon pain or rupture. With this integrative pathogenesis theory, we can relate the known manifestations of tendinopathy and point to the "missing links". This model may guide future research on tendinopathy, until we could ultimately decipher the complete pathogenesis process and provide better treatments.
doi:10.1186/1758-2555-2-30
PMCID: PMC3006368  PMID: 21144004
6.  Tendon degeneration and chronic shoulder pain: changes in the collagen composition of the human rotator cuff tendons in rotator cuff tendinitis. 
Annals of the Rheumatic Diseases  1994;53(6):359-366.
OBJECTIVES--To analyse the collagen composition of normal adult human supraspinatus tendon and to compare with: (1) a flexor tendon (the common biceps tendon) which is rarely involved in any degenerative pathology; (2) degenerate tendons from patients with chronic rotator cuff tendinitis. METHODS--Total collagen content, collagen solubility and collagen type were investigated by hydroxyproline analysis, acetic acid and pepsin digestion, cyanogen bromide peptide analysis, SDS-PAGE and Western blotting. RESULTS--The collagen content of the normal cadaver supraspinatus tendons (n = 60) was 96.3 micrograms HYPRO/mg dry weight (range 79.3-113.3) and there was no significant change across the age range 11 to 95 years. There was no significant difference from the common biceps tendon [93.3 (13.5) micrograms HYPRO/mg dry weight, n = 24]. Although extremely insoluble in both acetic acid and pepsin, much of the collagen was soluble after cyanogen bromide digestion [mean 47.9% (29.8)]. Seventeen per cent (10/60) of the 'normal' cadaver supraspinatus tendon sample contained more than 5% type III collagen, although none of the common biceps tendons had significant amounts. Degenerate supraspinatus and subscapularis tendons had a reduced collagen content [83.8 (13.9) micrograms/mg dry weight and 76.9 (16.8) micrograms/mg dry wt respectively) and were more soluble in acetic acid, pepsin and cyanogen bromide (p < 0.001). Eighty two per cent (14/17) of supraspinatus tendons and 100% (8/8) of subscapularis tendons from patients with tendinitis contained more than 5% type III collagen. CONCLUSIONS--The changes in collagen composition in rotator cuff tendinitis are consistent with new matrix synthesis, tissue remodelling and wound healing, in an attempt to repair the tendon defect, even in old and degenerate tendons. An increase in type III collagen in some 'normal' cadaver supraspinatus tendons is evidence that changes in collagen synthesis and turnover may precede tendon rupture. These changes may be the result of repeated minor injury and microscopic fibre damage or a consequence of local factors such as reduced vascular perfusion, tissue hypoxia, altered mechanical forces and the influence of cytokines. These collagenous changes may accumulate with age and substantially weaken the tendon structure, predisposing the tendon to rotator cuff tendinitis and eventual tendon rupture.
Images
PMCID: PMC1005350  PMID: 8037494
7.  VGluT2 expression in painful Achilles and patellar tendinosis: evidence of local glutamate release by tenocytes 
SUMMARY
BACKGROUND
The pathogenesis of chronic tendinopathy is unclear. We have previously measured high intratendinous levels of glutamate in patients with tendinosis, suggesting potential roles of glutamate in the modulation of pain, vascular function, and degenerative changes including apoptosis of tenocytes. However, the origin of free glutamate found in tendon tissue is completely unknown.
METHODS
Surgical biopsies of pain-free normal tendons and tendinosis tendons (Achilles and patellar) were examined immunohistochemically using antibodies against vesicular glutamate transporters (VGluT1 and VGluT2), as indirect markers of glutamate release. In situ hybridization for VGluT2 mRNA was also conducted.
RESULTS
Specific immunoreactions for VGluT2, but not VGluT1, could be consistently detected in tenocytes. However, there were interindividual variations in the levels of immunoreactivity. The level of immunoreaction for VGluT2 was higher in tendinosis tendons compared to normal tendon (p<0.05). In situ hybridization of VGluT2 demonstrated that mRNA was localized in a similar pattern as the protein, with marked expression by certain tenocytes, particularly those showing abnormal appearances. Reactivity for VGluT1 and -2 was absent from nerves and vessel structures in both normal and painful tendons.
CONCLUSIONS
The current data demonstrate that tenocytes may be involved in the regulation of extracellular glutamate levels in tendons. Specifically, the observations suggest that free glutamate may be locally produced and released by tenocytes, rather than by peripheral neurons. Excessive free glutamate is expected to impact a variety of autocrine and paracrine functions important in the development of tendinosis, including tenocyte proliferation and apoptosis, extracellular matrix metabolism, nociception and blood flow.
doi:10.1002/jor.20536
PMCID: PMC3951483  PMID: 18050306 CAMSID: cams4203
8.  Prevalence and possible pathological significance of calcium phosphate salt accumulation in tendon matrix degeneration. 
Annals of the Rheumatic Diseases  1996;55(2):109-115.
OBJECTIVES: To investigate the prevalence of calcium phosphate mineral salt accumulation in degenerative supraspinatus 'tendinitis' compared with a normal sample of human tendons, and to determine whether there is an association of calcium salt deposition with pathological changes in the tendon extracellular matrix. METHODS: Cadaver tendons (supraspinatus and common biceps tendons, n = 96) and fragments of supraspinatus tendons obtained during shoulder surgery (n = 31) were analysed for calcium content by atomic absorption spectroscopy, phosphorous content using a spectrophotometric assay, and matrix composition (collagen, glycosaminoglycans and DNA) using standard biochemical techniques. RESULTS: We established baseline values of calcium concentration in macroscopically normal cadaver tendons (mean 1.1 (SD 0.35) micrograms/mg dry wt, n = 60) and found that 33% (nine of 27) of ruptured tendons from patients with 'degenerative tendinitis' contained an excess of calcium (more than 2SD greater than the normal sample mean). Five of these specimens had increased concentrations of phosphorous and calcium:phosphorous (molar) ratios consistent with a variety of possible calcium crystals, including calcium pyrophosphate, hydroxyapatite, and tricalcium phosphate, in addition to mixed or amorphous calcium phosphate deposits. Four of these specimens contained normal concentrations of phosphorous, consistent with deposits of calcium oxalate or calcium carbonate, although this was not confirmed biochemically. In contrast, surgical specimens (n = 4) from patients with 'calcifying tendinitis' (radiographically detected calcium deposits) all contained salts with a mineral composition consistent with hydroxyapatite. The presence and identity of crystal deposits was subsequently confirmed in five specimens by radiographic microanalysis. Analysis of the tendon matrix demonstrated a number of significant differences between normal and degenerate (ruptured) tendons, including a reduction in collagen content, an increase in sulphated glycosaminoglycans (predominantly dermatan sulphate) and an increase in DNA (cellular) content. However, there were no significant differences between degenerate tendons that were 'calcified' and those degenerate specimens that contained normal concentrations of calcium. CONCLUSIONS: Although there was a relatively high prevalence of calcium salts in degenerate tendons, which might contribute to the pathological process (such as increased matrix collagen degradation), these data are consistent with the hypothesis that 'dystrophic calcification' of degenerate tendon matrix is a pathological entity distinct from cell mediated 'calcifying tendinitis'. Calcification is probably one possible outcome (or end point) of chronic tendon injury, although the possibility exists that in many cases, the presence of calcium salts may contribute to the tendon matrix degeneration.
PMCID: PMC1010104  PMID: 8712860
9.  P28 - Calcific Tendinopathy and Vitamin D Status: A Potential Aetiopathogenetic Factor and Therapeutic Approach 
Calcific tendinopathy is a common pain disorder of unclear origin characterised by the deposition of hydroxyapatite crystals in a tendon, most often in tendons of the rotator cuff of the shoulder. Degenerative changes in collagen fibres have been suggested to be responsible for dystrophic calcification. A local decrease in oxygen tension, not always due to chronic strain, may lead to reduction of pH in a critical region, with fibrocartilaginous metaplasia and resultant calcification. Rotator cuff calcification occurs in 3–8% of healthy shoulders in adults, more frequently in women, during the 4th–6th decades of life, sometimes bilaterally.
In a group of 30 subjects (20 women, 10 men; mean age 51.1, range 27–63 years) with rotator cuff calcification, treated with two-needle US-guided percutaneous treatment, we analysed phospho-calcium metabolism markers (calcaemia, phosphorus, magnesium, 25-OH vitamin D, 1,25(OH)2-vitamin D, calciuria, phosphaturia and PTH). 28 patients showed a low level of 25-OH vitamin D (mean value: 16.96 ng/mL, 3–26 ng/mL), calcitriol at or above the upper limits (mean value: 62.77 pg/mL), and PTH concentration in line with the 25OHD levels, most frequently at the upper normal limits. Urinary levels of calcium and phosphorus were at or below the lower limits.
Vitamin D, as well as enhancing intestinal absorption of calcium, plays an important role in the regulation of bone mineralisation, stimulating both RANKL and osteoprotegerin expression. A transient hyperparathyroidism secondary to vitamin D deficiency may be at the origin of heterotopic calcifications in patients with rotatory cuff tendinopathy. Administration of 25OHD, by reducing transient increases of PTH and directly acting on connective tissue cells, could probably reduce the phenomenon or even prevent it.
PMCID: PMC3213790
10.  Sclerosing therapy and eccentric training in flexor carpi radialis tendinopathy in a tennis player 
British Journal of Sports Medicine  2007;41(12):920-921.
Background
Tendinopathy of the flexor carpi ulnaris tendon is a rare entity. Recent research revealed the role of a neurovascular ingrowth at the point of pain in various tendinopathic locations, such as at the Achilles and patellar tendon, in plantar fasciitis as well as in supraspinatus and tennis elbow tendinopathy. However, beyond the elbow no such neovascularisation has been reported to date.
Methods
We present a 35‐year old tennis player suffering tremendous pain (visual analogue scale (VAS) rating of 9/10) at the flexor carpi ulnaris tendon with adjacent calcification in close proximity to the pisiform bone. The patient was assessed with power Doppler and laser Doppler quantification of neovascularisation at the point of pain.
Results
Power Doppler and laser Doppler quantification of neovascularisation at the point of pain identified higher capillary blood flow at three points over the painful vs the non‐painful tendon (146/240/232rU vs 93/74/70rU at the non‐affected side). Sclerosing therapy using polidocanol under power and laser Doppler guidance was initiated, with immediate decrease of capillary blood flow by 25% with resolution of the neovascularisation in power Doppler. Immediately following sclerosing, the patient's reported pain level on the VAS was reduced from 9/10 to 4/10. Following a short period of rest, eccentric training of the forearm muscle was initiated over 12 weeks with functional complete recovery and complete resolution of wrist pain.
Conclusion
Sclerosing therapy using polidocanol under power‐ and laser‐Doppler guidance can decrease capillary blood flow by 25% with resolution of the neovascularisation. Subsequent eccentric training of the forearm muscle over 12 weeks can result in complete resolution of wrist pain.
doi:10.1136/bjsm.2007.036558
PMCID: PMC2659004  PMID: 17496066
11.  Effect of prostaglandin E2 injection on the structural properties of the rat patellar tendon 
Background
Increased tendon production of the inflammatory mediator prostaglandin E2 (PGE2) has been suggested to be a potential etiologic agent in the development of tendinopathy. Repeated injection of PGE2 into tendon has been proposed as a potential animal model for studying treatments for tendinopathy. In contrast, nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit PGE2 production and are commonly prescribed in treating tendinopathy have been shown to impair the healing of tendon after acute injury in animal models. The contradictory literature suggests the need to better define the functional effects of PGE2 on tendon. Our objective was to characterize the effects of PGE2 injection on the biomechanical and biochemical properties of tendon and the activity of the animals. Our hypothesis was that weekly PGE2 injection to the rat patellar tendon would lead to inferior biomechanical properties.
Methods
Forty rats were divided equally into four groups. Three groups were followed for 4 weeks with the following peritendinous injection procedures: No injection (control), 4 weekly injections of saline (saline), 4 weekly injections of 800 ng PGE2 (PGE2-4 wks). The fourth group received 4 weekly injections of 800 ng PGE2 initially and was followed for a total of 8 weeks. All animals were injected bilaterally. The main outcome measurements included: the structural and material properties of the patellar tendon under tensile loading to failure, tendon collagen content, and weekly animal activity scores.
Results
The ultimate load of PGE2-4 wks tendons at 4 weeks was significantly greater than control or saline group tendons. The stiffness and elastic modulus of the PGE2 injected tendons at 8 weeks was significantly greater than the control or saline tendons. No differences in animal activity, collagen content, or mean fibril diameter were observed between groups.
Conclusions
Four weekly peritendinous injections of PGE2 to the rat patellar tendon were not found to be an effective model of clinical tendinopathy. In contrast, improved structural and material properties of the patellar tendon were found after PGE2 injection. While PGE2 has been thought to have a contributory role in the development of tendinopathy and anti-inflammatory medications remain a common treatment, our results suggest a positive role of PGE2 in tendon remodeling in some circumstances.
doi:10.1186/1758-2555-4-2
PMCID: PMC3271034  PMID: 22230219
12.  Achilles tendon suture deteriorates tendon capillary blood flow with sustained tissue oxygen saturation – an animal study 
Background
Treatment of ruptured Achilles tendons currently constitutes of conservative early functional treatment or surgical treatment either by open or minimal invasive techniques. We hypothesize that an experimental Achilles tendon suture in an animal model significantly deteriorates Achilles tendon microcirculation immediately following suturing.
Methods
Fifteen Achilles tendons of eight male Wistar rats (275–325 g) were included. After preparation of the Achilles tendon with a medial paratendinous approach, Achilles tendon microcirculation was assessed using combined Laser-Doppler and spectrophotometry (Oxygen-to-see) regarding:
- tendinous capillary blood flow [arbitrary units AU]
- tendinous tissue oxygen saturation [%]
- tendinous venous filling pressure [rAU]
The main body of the Achilles tendon was measured in the center of the suture with 50 Hz. 10 minutes after Achilles tendon suture (6-0 Prolene), a second assessment of microcirculatory parameters was performed.
Results
Achilles tendon capillary blood flow decreased by 57% following the suture (70 ± 30 AU vs. 31 ± 16 AU; p < 0.001). Tendinous tissue oxygen saturation remained at the same level before and after suture (78 ± 17% vs. 77 ± 22%; p = 0.904). Tendinous venous filling pressure increased by 33% (54 ± 16 AU vs. 72 ± 20 AU; p = 0.019) after suture.
Conclusion
Achilles tendon suture in anaesthetised rats causes an acute loss of capillary perfusion and increases postcapillary venous filling pressures indicating venous stasis. The primary hypothesis of this study was confirmed. In contrast, tendinous tissue oxygen saturation remains unchanged excluding acute intratendinous hypoxia within the first 10 minutes after suture. Further changes of oxygen saturation remain unclear. Furthermore, it remains to be determined to what extent reduced capillary blood flow as well as increased postcapillary stasis might influence tendon healing from a microcirculatory point of view in this animal setting.
doi:10.1186/1749-799X-4-32
PMCID: PMC2731078  PMID: 19674439
13.  Experimental Diabetes Induces Structural, Inflammatory and Vascular Changes of Achilles Tendons 
PLoS ONE  2013;8(10):e74942.
This study aims to demonstrate how the state of chronic hyperglycemia from experimental Diabetes Mellitus can influence the homeostatic imbalance of tendons and, consequently, lead to the characteristics of tendinopathy. Twenty animals were randomly divided into two experimental groups: control group, consisting of healthy rats and diabetic group constituted by rats induced to Diabetes Mellitus I. After twenty-four days of the induction of Diabetes type I, the Achilles tendon were removed for morphological evaluation, cellularity, number and cross-sectional area of blood vessel, immunohistochemistry for Collagen type I, VEGF and NF-κB nuclear localization sequence (NLS) and nitrate and nitrite level. The Achilles tendon thickness (µm/100g) of diabetic animals was significantly increased and, similarly, an increase was observed in the density of fibrocytes and mast cells in the tendons of the diabetic group. The average number of blood vessels per field, in peritendinous tissue, was statistically higher in the diabetic group 3.39 (2.98) vessels/field when compared to the control group 0.89 (1.68) vessels/field p = 0.001 and in the intratendinous region, it was observed that blood vessels were extremely rare in the control group 0.035 (0.18) vessels/field and were often present in the tendons of the diabetic group 0.89 (0.99) vessels/field. The immunohistochemistry analysis identified higher density of type 1 collagen and increased expression of VEGF as well as increased immunostaining for NFκB p50 NLS in the nucleus in Achilles tendon of the diabetic group when compared to the control group. Higher levels of nitrite/nitrate were observed in the experimental group induced to diabetes. We conclude that experimental DM induces notable structural, inflammatory and vascular changes in the Achilles tendon which are compatible with the process of chronic tendinopathy.
doi:10.1371/journal.pone.0074942
PMCID: PMC3794027  PMID: 24130676
14.  Glycosaminoglycans of human rotator cuff tendons: changes with age and in chronic rotator cuff tendinitis. 
Annals of the Rheumatic Diseases  1994;53(6):367-376.
OBJECTIVES--To analyse the glycosaminoglycans of the adult human rotator cuff tendon matrix, to characterise changes in the glycosaminoglycan composition with age and in chronic rotator cuff tendinitis. METHODS--Rotator cuff (supraspinatus) tendons (n = 84) and common biceps tendons (n = 26) were obtained from cadavers with no history of tendon pathology (age range 11-95 years). Biopsies of rotator cuff tendons (supraspinatus and subscapularis tendons, n = 53) were obtained during open shoulder surgery to repair shoulder lesions (age range 38-80 years). Glycosaminoglycans were extracted by papain digestion and analysed by cellulose acetate electrophoresis, the carbazole assay for uronic acid and the dimethylmethylene blue dye-binding assay for sulphated glycosaminoglycans. Some digests were analysed for keratan sulphate by 5D4 monoclonal antibody ELISA. Soluble proteoglycans were extracted in 4M guanidine hydrochloride and analysed by 4-15% SDS PAGE. RESULTS--The mean (SD) sulphated glycosaminoglycan (GAG) content of the normal cadaver supraspinatus tendon was 12.3 (4.3) micrograms/mg dry weight, between three and ten times greater than in the common biceps tendon [1.2 (0.6) micrograms/mg dry weight]. The major GAG was chondroitin sulphate [6.9 (2.6) micrograms/mg dry weight], with a smaller proportion of dermatan sulphate [2.5 (1.2) micrograms/mg dry weight]. In contrast, the common biceps tendon contained predominantly dermatan sulphate [0.8 (0.2) microgram/mg dry weight] with less chondroitin sulphate [0.2 (0.2) microgram/mg dry weight]. There was no difference in the concentration of hyaluronan in these tendons [9.3 (2.8) micrograms/mg dry weight and 10.8 (4.3) micrograms/mg dry weight respectively] and there was no significant change of hyaluronan with age. Keratan sulphate was a small but significant component of the supraspinatus tendon [0.43 (0.33) microgram/mg dry weight, n = 25], whereas there was little or none in the common biceps tendon [0.04 (0.05) microgram/mg dry weight, n = 8] and there was no significant change across the age range. In the supraspinatus tendon, there was a significant decrease in total glycosaminoglycan, chondroitin sulphate and dermatan sulphate with age (p < 0.001), whether expressed relative to the tendon dry weight or total collagen content, and no change in the relative proportion of the different GAG types. There was, however, a large degree of variation within the samples. Supraspinatus tendons from patients with chronic tendinitis had a significantly increased concentration of hyaluronan [30.4 (10.1) micrograms/mg dry weight, p < 0.001], chondroitin sulphate [8.4 (1.8) micrograms/mg dry weight, p < 0.05] and dermatan sulphate [3.8 (1.1) micrograms/mg dry weight, p < 0.001] compared with normal cadaver supraspinatus tendons, although the keratan sulphate content was not significantly different [0.18 (0.05) microgram/mg dry weight]. CONCLUSIONS--The normal supraspinatus tendon has the proteoglycan/glycosaminoglycan of tendon fibrocartilage, which it is suggested is an adaptation to mechanical forces (tension, compression and shear) which act on the rotator cuff tendons in the shoulder, although other factors such as reduced vascularity, low oxygen tension and the influence of local growth factors may also be important. This functional adaptation may have important consequences for the structural strength of the supraspinatus tendon and to influence the ability of the tendon to repair after injury. The glycosaminoglycan composition of tendon specimens from patients with chronic tendinitis is consistent with acute inflammation and new matrix proteoglycan synthesis, even in relatively old tendon specimens and after at least one injection of corticosteroid.
Images
PMCID: PMC1005351  PMID: 8037495
15.  Arthroscopic Treatment of Calcific Tendonitis 
Arthroscopy Techniques  2014;3(2):e237-e240.
Calcific tendonitis, or calcifying tendonitis, is a common disorder characterized by the multifocal accumulation of basic calcium phosphate crystals within the rotator cuff tendons. In most cases, the multifocal calcifications are located 1 to 2 cm from the insertion of the supraspinatus tendon on the greater tuberosity. The initial treatment should be nonoperative including oral anti-inflammatory medication and physical therapy. If this is unsuccessful, arthroscopic debridement of the deposit is effective. The technique used is an arthroscopic localization and debridement without associated subacromial decompression. The rotator cuff should be evaluated for partial- and full-thickness tears before and after the debridement of calcifications. If a partial- or full-thickness rotator cuff tendon tear is identified, it should be treated in a fashion consistent with those without associated calcium deposits. In our hands, tears 5 mm or greater in depth are repaired using a tendon-to-tendon or tendon-to-bone technique. Tears with less depth are debrided and then left alone. Arthroscopic debridement of calcific tendonitis can yield excellent functional results and high patient satisfaction.
doi:10.1016/j.eats.2013.11.003
PMCID: PMC4044535  PMID: 24904767
16.  Tendon Properties Remain Altered in a Chronic Rat Rotator Cuff Model 
Background
Chronic rotator cuff tears are often associated with pain or poor function. In a rat with only a detached supraspinatus tendon, the tendon heals spontaneously which is inconsistent with how tears are believed to heal in humans.
Questions/purposes
We therefore asked whether a combined supraspinatus and infraspinatus detachment in the rat would fail to heal and result in a chronic injury in the supraspinatus tendon.
Methods
We acutely detached the supraspinatus and infraspinatus tendons in a rat model. At 4, 8, and 16 weeks post-detachment, biomechanical testing, collagen organization, and histological grading were evaluated for the detached supraspinatus and infraspinatus tendons and compared to controls.
Results
In the detached supraspinatus tendon, area and percent relaxation were increased at all time points while the modulus and stiffness were similar to those of controls at 4 and 8 weeks. Collagen disorganization increased at late time points while cellularity increased and cells were more rounded in shape. In the detached infraspinatus tendon, area and percent relaxation were also increased at late time points. However, the modulus values initially decreased followed by an increase in both modulus and stiffness at 16 weeks compared to control. In the detached infraspinatus, we also observed a decrease in collagen organization at all time points and increased cellularity and a more rounded cell shape.
Conclusions
Due to the ongoing changes in mechanics, collagen organization and histology in the detached supraspinatus tendon compared to control animals at 16 weeks, this model may be useful for understanding the human chronic tendon tear.
Clinical Relevance
This rat rotator cuff chronic model can be used to test hypotheses regarding injury and repair mechanisms that cannot be addressed in human patients or in cadaveric studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-009-1206-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-009-1206-y
PMCID: PMC2865621  PMID: 20049569
17.  Eccentric training in Achilles tendinopathy: is it harmful to tendon microcirculation? 
Background
Eccentric training has been shown to reduce pain and gain function in patients with chronic Achilles tendinopathy. However, currently no data are available regarding any potential adverse effects of an eccentric training intervention on Achilles tendon microcirculation.
Methods
59 patients (49 (12) years; body mass index 27 (5); 49 mid‐portion, 10 chronic insertional tendinopathy) with 64 symptomatic (54 mid‐portion, 10 insertional) Achilles tendons were prospectively enrolled. Baseline tendon microcirculation at four distinct tendon positions from the insertion to the proximal mid‐portion area was assessed using a laser Doppler system for capillary blood flow, tissue oxygen saturation and postcapillary venous filling pressure. A 12‐week daily painful home‐based eccentric training regimen was initiated (3×15 repetitions per tendon and day).
Results
Achilles tendon capillary blood flow was significantly reduced at the insertion (by 35%, p = 0.008) and the distal mid‐portion area (by 45%, p = 0.015) at 2 mm and by 22% (p = 0.007) and 13% (p = 0.122) at 8 mm tissue depths, respectively. Achilles tendon oxygen saturation was not decreased after the 12‐week eccentric training regimen throughout the insertion to the proximal mid‐portion area (insertion 72 (13) vs 73 (10), proximal mid‐portion 63 (13) vs 62 (11), both NS). Achilles tendon postcapillary venous filling pressures were significantly reduced at the insertion (51 (16) vs 41 (19), p = 0.001) and the distal mid‐portion (36 (13) vs 32 (12), p = 0.037) at 2 mm and at the insertion at 8 mm (63 (19) vs 51 (13), p = 0.0001). Pain was reduced from 5.4 (2.1) to 3.6 (2.4; p = 0.001) in the mid‐portion and from 6 (2.5) to 3.2 (2.7; p = 0.002) in the insertional tendinopathy group. No Achilles tendon rupture or any interruption during the eccentric training was noted among the 59 patients.
Conclusion
Daily eccentric training for Achilles tendinopathy is a safe and easy measure, with beneficial effects on the microcirculatory tendon levels without any evident adverse effects in both mid‐portion and insertional Achilles tendinopathy.
doi:10.1136/bjsm.2006.030437
PMCID: PMC2465326  PMID: 17127721
18.  Tendon injury and repair after core biopsies in chronic Achilles tendinosis evaluated by serial magnetic resonance imaging 
Objective: To evaluate the morphological response and healing process after transverse ultrasound guided core biopsies in chronic Achilles tendinosis using serial magnetic resonance imaging (MRI) over a period of one year.
Methods: The study included 10 patients. Six had five transverse core biopsies and were longitudinally evaluated by MRI before the biopsies and then after one week, three months, seven months, and one year. These patients started a three month eccentric training programme one to two weeks after the biopsy. Four "non-biopsied" and untreated patients were used for comparison. The clinical outcome was categorised according to the level of pain and performance.
Results: The MRI one week after the biopsies showed an increase in tendon volume (T1-WI) and mean signal intensity (PD-WI) of 29% and 30% (p = 0.04). During follow up, tendon volume and mean signal intensity gradually decreased. One year after the biopsy, the tendon volume had decreased by 20% and the intratendinous signal by 28% compared with the index MRI (p = 0.04). The untreated patients showed an increase in both tendon volume (39%, p = 0.06) and intratendinous signal (37%, p = 0.14) at the one year follow up. After one year, pain and performance had improved in the treated patients but not the untreated patients.
Conclusion: Five transverse ultrasound guided core biopsies induced a lesion in the diseased Achilles tendon. Alterations during healing such as tendon size and intratendinous signal intensity could be evaluated by MRI. The tendon alterations had decreased one year after the core biopsies.
doi:10.1136/bjsm.2003.007609
PMCID: PMC1724913  PMID: 15388549
19.  Ultrasound-guided injection of platelet-rich plasma in chronic Achilles and patellar tendinopathy☆ 
Journal of Ultrasound  2012;15(4):260-266.
Purpose
The efficacy of platelet-rich plasma (PRP) in the treatment and healing of chronic tendinopathy through stimulation of cell proliferation and total collagen production has been demonstrated by both in vitro and in vivo studies. The aim of this study is to evaluate the effectiveness of ultrasound (US)-guided autologous PRP injections in patellar and Achilles tendinopathy.
Materials and methods
Autologous PRP was injected under US-guidance into the Achilles and patellar tendons (30 Achilles tendons, 28 patellar tendons) in 48 prospectively selected patients (30 males, 18 females, mean age 38 ± 16 years, range 20–61 years). All patients were previously evaluated according to the Victoria Institute of Sport Assessment (VISA) scale, which assessed pain and activity level, and they all underwent US of the tendon before treatment and at follow-up after 20 days and 6 months. Statistical analysis was performed with Chi-square and Wilcoxon tests.
Results
20 days after PRP injection the patients presented a non-significant improvement of clinical symptoms. At the 6-month follow-up VISA score increased from a mean value of 57–75.5 (p < .01). US evaluation revealed a reduction of hypoechoic areas in 26 tendons (p < .01) associated with a widespread improvement of fibrillar echotexture of the tendon and reduced hypervascularity at power Doppler.
Conclusion
PRP injection in patellar and Achilles tendinopathy results in a significant and lasting improvement of clinical symptoms and leads to recovery of the tendon matrix potentially helping to prevent degenerative lesions. US-guidance allows PRP injection into the tendon with great accuracy.
doi:10.1016/j.jus.2012.09.006
PMCID: PMC3558233  PMID: 23730392
Platelet-rich plasma; Achilles tendon; Patellar tendon; Jumper's knee; Achilles tendinopathy
20.  The “bench‐presser's shoulder”: an overuse insertional tendinopathy of the pectoralis minor muscle 
Background
Tendinopathies of the rotator cuff muscles, biceps tendon and pectoralis major muscle are common causes of shoulder pain in athletes. Overuse insertional tendinopathy of pectoralis minor is a previously undescribed cause of shoulder pain in weightlifters/sportsmen.
Objectives
To describe the clinical features, diagnostic tests and results of an overuse insertional tendinopathy of the pectoralis minor muscle. To also present a new technique of ultrasonographic evaluation and injection of the pectoralis minor muscle/tendon based on use of standard anatomical landmarks (subscapularis, coracoid process and axillary artery) as stepwise reference points for ultrasonographic orientation.
Methods
Between 2005 and 2006, seven sportsmen presenting with this condition were diagnosed and treated at the Cape Shoulder Institute, Cape Town, South Africa.
Results
In five patients, the initiating and aggravating factor was performance of the bench‐press exercise (hence the term “bench‐presser's shoulder”). Medial juxta‐coracoid tenderness, a painful active‐contraction test and bench‐press manoeuvre, and decrease in pain after ultrasound‐guided injection of a local anaesthetic agent into the enthesis, in the absence of any other clinically/radiologically apparent pathology, were diagnostic of pectoralis minor insertional tendinopathy. All seven patients were successfully treated with a single ultrasound‐guided injection of a corticosteroid into the enthesis of pectoralis minor followed by a period of rest and stretching exercises.
Conclusions
This study describes the clinical features and management of pectoralis minor insertional tendinopathy, secondary to the bench‐press type of weightlifting. A new pain site‐based classification of shoulder pathology in weightlifters is suggested.
doi:10.1136/bjsm.2006.032383
PMCID: PMC2465431  PMID: 17138640
21.  Addition of Nitric Oxide Through Nitric Oxide-paracetamol Enhances Healing Rat Achilles Tendon 
Nitric oxide is an important messenger molecule in many physiological processes. The addition of NO via NO-flurbiprofen enhances the material properties of healing tendon, however, flurbiprofen has a detrimental effect on healing. We asked if NO delivered by a cyclooxygenase 3 inhibitor (paracetamol/acetaminophen) would enhance healing in a rat Achilles tendon healing model. Rats were injected subcutaneously daily with NO-paracetamol, paracetamol or vehicle from two days before surgery to the day of tissue harvesting. Paracetamol had no effect on tendon healing compared with vehicle alone. NO-paracetamol did not change the failure load, but did decrease the water content, enhance the collagen content, reduce the cross-sectional area and improve the ultimate stress of healing tendon compared with paracetamol and vehicle. The collagen organization of the healing tendon in the NO-paracetamol group, as determined by polarized light microscopy, was enhanced. Our data suggests NO-paracetamol increases the total collagen content and enhances organization while decreasing the cross-sectional area of healing rat Achilles tendon and is consistent with human clinical trials where NO has improved the symptoms and signs of tendinopathy.
doi:10.1007/s11999-008-0271-y
PMCID: PMC2505261  PMID: 18463933
22.  Ultrasonograph and Clinical Quantitative Characterization of Tendinopathy by Modified Splitting in a Goat Model 
The Scientific World Journal  2012;2012:472023.
A tendinopathy is a clinical condition characterized by activity-related pain, focal tendons tenderness, and intratendinous imaging changes. This study characterizes a surgically induced tendinopathy in a goat model with a noninvasive in vivo longitudinal followup based on physical examination and US. Cross-sectional area (CSA) is the most objective feature for the evaluation of tendinopathy in correlation with clinical findings. The deep digital flexor tendon (DDFT) of the left hind limb of six goats was isolated and scarified by a modified splitting. Pain and lameness at walk and trot were evaluated. External width and thickness of tendon region were measured by calipers. CSA and the ratio lesion/tendon CSA were obtained at days 0, 7, 21, 42, and 84 by US. The highest value of global functional score was obtained at day 7, then decreased until day 40 and was not significantly different from day 0 at the end of the study. The external width recovered a normal value at the end of the study, but the external thickness was still significantly increased (P < 0.05). Peritendinous oedema was observed at day 7, but intratendinous lesions were visible only at day 21 as a focal hypo to anechoic area. At day 84, two tendons still presented visible lesions. US examination was reproducible, specific, and provided complementary information to the global functional score. A standardized focal tendinopathy was induced in goats. This experimental model of focal tendinopathy could be used to study the effect of different treatments.
doi:10.1100/2012/472023
PMCID: PMC3444857  PMID: 22997496
23.  Ultrasound assessment of elbow enthesitis in patients with seronegative arthropathies 
Journal of Ultrasound  2013;17(1):33-40.
Background
Enthesopathy is an evolving area for applied clinical research. MRI is the gold standard in the diagnosis of elbow joint pathology, but recent reports indicate that ultrasound imaging is more sensitive and accurate than MRI in detecting enthesopathy of the heels and knees. Too many patients are under-diagnosed and/or misdiagnosed because the early pathological changes of enthesitis in the different types of seronegative arthropathies are not detected.
Objectives
This study was undertaken to describe the ultrasound features of elbow enthesitis in patients with seronegative arthropathies.
Methods
We studied 38 diseased elbows in 38 patients with spondyloarthropathies (26 men and 12 women, mean age 32 years). All had elbow enthesopathy without typical conventional radiographic findings. Patients with histories of degenerative changes and/or local steroid injections were excluded. An HDI 3000 ATL ultrasound machine was used with a 5–12 MHz linear transducer to examine the affected elbow joints. The elbows of 10 normal healthy individuals were examined as normal controls. The patients were examined in the supine position with the elbow flexed 30°–50°. Longitudinal and transverse scans were obtained of the radiohumeral joint, the ulnahumeral joint, and the olecranon fossa. Two independent observers unaware of the clinical diagnosis read the ultrasound images and assessed the collateral ligaments, intratendinous echogenicity, tendon calcification, tendon thickness, presence of fluid, synovial proliferation, and bony changes. The reliability of the sonographic images was assessed by review of video recordings of the ultrasound examinations.
Results
Ultrasound revealed loss of the fibrillar echopattern (100 %), lack of a homogenous pattern with loss of the tightly packed echogenic dots (100 %), peritendinous edema with flaring of the tendon margins (84.2 %), irregular fusiform tendon thickening (100 %), and hyperechoic intratendinous lesions with ill-defined focal defects (18.4 %). Ultrasound also detected intratendinous calcifications of both the common extensor and common flexor tendons (52.6 %). Bony erosions were seen at the tendon insertions into the lateral epicondyles (13.15 %).
Conclusion
Ultrasonographic features of elbow enthesitis differed from those described in knee and heel enthesitis. Ultrasound clearly showed early signs of tendon calcification, tendon edema, peritendinitis, and bony entheseal erosions. However, in elbow enthesitis the early bone erosion was associated with bone marrow edema, and the common extensor tendon was diffusely thickened. Ultrasound is a reliable, reproducible bedside imaging procedure. It improves the documentation of disease activity, progression, and treatment responses in patients with spondyloarthropathies. We recommend its use for the diagnosis and post-treatment follow-up of patients with enthesitis and seronegative spondyloarthropathies.
doi:10.1007/s40477-013-0057-2
PMCID: PMC3945195  PMID: 24616743
Ultrasound; Elbow enthesitis; Seronegative arthropathies
24.  Aprotinin in the management of Achilles tendinopathy: a randomised controlled trial 
Background
Achilles tendinopathy is a common condition, which can become chronic and interfere with athletic performance. The proteinase inhibitor aprotinin (as injection) has been found to improve recovery in patellar tendinopathy1 (evidence level 1b2) and Achilles tendinopathy.3 Internationally this therapy is being used based on this limited knowledge base.
Aim
To evaluate whether aprotinin injections decrease time to recovery in Achilles tendinopathy.
Method
A prospective, randomised, double blind, placebo controlled trial was performed comparing saline (0.9%) plus local anaesthetic injections and eccentric exercises with aprotinin (30 000 kIU) plus local anaesthetic injection and eccentric exercise. Three injections were given, each a week apart. In total, 26 patients, with 33 affected tendons, were enrolled for this study.
Results
At no follow up point (2, 4, 12, or 52 weeks) was there any statistically significant difference between the treatment group and placebo. This included VISA‐A scores4 and secondary outcome measures. However, a trend for improvement over placebo was noted.
Conclusion
In this study on Achilles tendinopathy, aprotinin was not shown to offer any statistically significant benefit over placebo. Larger multicentre trials are needed to evaluate the efficacy of aprotinin in Achilles tendinopathy.
doi:10.1136/bjsm.2005.021931
PMCID: PMC2491994  PMID: 16505089
Achilles; tendinopathy
25.  Platelet-rich plasma injections for the treatment of refractory Achilles tendinopathy: results at 4 years 
Blood Transfusion  2014;12(4):533-540.
Background
Chronic Achilles tendinopathy is responsible for a severe reduction in physical performance and persistent pain. There is currently a number of therapeutic options and the local administration of growth factors is an emerging treatment strategy. In particular, platelet-rich plasma (PRP) is a widely used way to provide a local regenerative stimulus for tendon healing. The aim of this study was to document the mid-term results obtained after treating recalcitrant Achilles tendinopathy with injections of high concentrate, leucocyte-rich PRP.
Materials and methods
Twenty-seven patients (mean age: 44.6 years; 22 men and 5 women) affected by chronic mid-portion Achilles tendinopathy (7 bilateral, for a total of 34 tendons), refractory to previous treatments, were enrolled. Patients were treated with three ultrasound-guided intra-tendinous injections of PRP at 2-week intervals. Patients were prospectively evaluated at baseline, and then at 2, 6, and up to a mean of 54.1 months of follow-up (minimum 30 months), using the following tools: Blanzina, VISA-A, EQ-VAS for general health, and Tegner scores.
Results
The VISA-A score showed a significant improvement: the baseline score of 49.9±18.1 increased to 62.9±19.8 at 2 months (p=0.002), with a further improvement at 6 months (84.3±17.1, p<0.0005), and stable results at 4.5 years (90.0±13.9). The EQ-VAS score also showed a similar positive trend. An evaluation of the activity level confirmed these findings, showing a significant improvement in the Tegner score over time (p=0.017 for the final evaluation). The longer duration of symptoms before treatment was associated with a slower return to sport (p=0.041).
Discussion
PRP injections produced good overall results for the treatment of chronic recalcitrant Achilles tendinopathy with a stable outcome up to a medium-term follow-up. Longer symptom duration was related with a more difficult return to sporting activity.
doi:10.2450/2014.0289-13
PMCID: PMC4212034  PMID: 24960641
PRP; growth factors; Achilles tendinopathy; injections; long term

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