M. Kongsgaard

Corticosteroid injections, eccentric decline squat training and heavy slow resistance training in patellar tendinopathy.

A randomized‐controlled single‐blind trial was conducted to investigate the clinical, structural and functional effects of peritendinous corticosteroid injections (CORT), eccentric decline squat training (ECC) and heavy slow resistance training (HSR) in patellar tendinopathy. Thirty‐nine male patients were randomized to CORT, ECC or HSR for 12 weeks. We assessed function and symptoms (VISA‐p questionnaire), tendon pain during activity (VAS), treatment satisfaction, tendon swelling, tendon vascularization, tendon mechanical properties and collagen crosslink properties. Assessments were made at 0 weeks, 12 weeks and at follow‐up (half‐year). All groups improved in VISA‐p and VAS from 0 to 12 weeks (P<0.05). VISA‐p and VAS improvements were maintained at follow‐up in ECC and HSR but deteriorated in CORT (P<0.05). In CORT and HSR, tendon swelling decreased (−13±9% and −12±13%, P<0.05) and so did vascularization (−52±49% and −45±23%, P<0.01) at 12 weeks. Tendon mechanical properties were similar in healthy and injured tendons and were unaffected by treatment. HSR yielded an elevated collagen network turnover. At the half‐year follow‐up, treatment satisfaction differed between groups, with HSR being most satisfied. Conclusively, CORT has good short‐term but poor long‐term clinical effects, in patellar tendinopathy. HSR has good short‐ and long‐term clinical effects accompanied by pathology improvement and increased collagen turnover.

From mechanical loading to collagen synthesis, structural changes and function in human tendon

The adaptive response of connective tissue to loading requires increased synthesis and turnover of matrix proteins, with special emphasis on collagen. Collagen formation and degradation in the tendon increases with both acute and chronic loading, and data suggest that a gender difference exists, in that females respond less than males with regard to an increase in collagen formation after exercise. It is suggested that estrogen may contribute toward a diminished collagen synthesis response in females. Conversely, the stimulation of collagen synthesis by other growth factors can be shown in both animal and human models where insulin‐like growth factor 1 (IGF‐I) and transforming growth factor‐β‐1 (TGF‐β‐1) expression increases to accompany or precede an increase in procollagen expression and collagen synthesis. In humans, it can be demonstrated that an increase in the interstitial concentration of TGF‐β, PGE2, IGF‐I plus its binding proteins and interleukin‐6 takes place after exercise. The increase in IGF‐I expression in tendon includes the isoform that has so far been thought only to exist in skeletal muscle (mechano growth factor). The increase in IGF‐I and procollagen expression showed a similar response whether the tendon was stimulated by concentric, isometric or eccentric muscle contraction, suggesting that strain rather that stress/torque determines the collagen‐synthesis stimulating response seen with exercise. The adaptation time to chronic loading is longer in tendon tissue compared with contractile elements of skeletal muscle or the heart, and only with very prolonged loading are significant changes in gross dimensions of the tendon observed, suggesting that habitual loading is associated with a robust change in the size and mechanical properties of human tendons. An intimate interplay between mechanical signalling and biochemical changes in the matrix is needed in tendon, such that chemical changes can be converted into adaptations in the morphology, structure and material properties.

Habitual loading results in tendon hypertrophy and increased stiffness of the human patellar tendon

The purpose of this study was to examine patellar tendon (PT) size and mechanical properties in subjects with a side-to-side strength difference of > or =15% due to sport-induced loading. Seven elite fencers and badminton players were included. Cross-sectional area (CSA) of the PT obtained from MRI and ultrasonography-based measurement of tibial and patellar movement together with PT force during isometric contractions were used to estimate mechanical properties of the PT bilaterally. We found that distal tendon and PT, but not mid-tendon, CSA were greater on the lead extremity compared with the nonlead extremity (distal: 139 +/- 11 vs. 116 +/- 7 mm(2); mid-tendon: 85 +/- 5 vs. 77 +/- 3 mm(2); proximal: 106 +/- 7 vs. 83 +/- 4 mm(2); P < 0.05). Distal tendon CSA was greater than proximal and mid-tendon CSA on both the lead and nonlead extremity (P < 0.05). For a given common force, stress was lower on the lead extremity (52.9 +/- 4.8 MPa) compared with the nonlead extremity (66.0 +/- 8.0 MPa; P < 0.05). PT stiffness was also higher in the lead extremity (4,766 +/- 716 N/mm) compared with the nonlead extremity (3,494 +/- 446 N/mm) (P < 0.05), whereas the modulus did not differ (lead 2.27 +/- 0.27 GPa vs. nonlead 2.16 +/- 0.28 GPa) at a common force. These data show that a habitual loading is associated with a significant increase in PT size and mechanical properties.

Mechanical properties and collagen cross-linking of the patellar tendon in old and young men

Age-related loss in muscle mass and strength impairs daily life function in the elderly. However, it remains unknown whether tendon properties also deteriorate with age. Cross-linking of collagen molecules provides structural integrity to the tendon fibrils and has been shown to change with age in animals but has never been examined in humans in vivo. In this study, we examined the mechanical properties and pyridinoline and pentosidine cross-link and collagen concentrations of the patellar tendon in vivo in old (OM) and young men (YM). Seven OM (67 +/- 3 years, 86 +/- 10 kg) and 10 YM (27 +/- 2 years, 81 +/- 8 kg) with a similar physical activity level (OM 5 +/- 6 h/wk, YM 5 +/- 2 h/wk) were examined. MRI was used to assess whole tendon dimensions. Tendon mechanical properties were assessed with the use of simultaneous force and ultrasonographic measurements during ramped isometric contractions. Percutaneous tendon biopsies were taken and analyzed for hydroxylysyl pyridinoline (HP), lysyl pyridinoline (LP), pentosidine, and collagen concentrations. We found no significant differences in the dimensions or mechanical properties of the tendon between OM and YM. Collagen concentrations were lower in OM than in YM (0.49 +/- 0.27 vs. 0.73 +/- 0.14 mg/mg dry wt; P < 0.05). HP concentrations were higher in OM than in YM (898 +/- 172 vs. 645 +/- 183 mmol/mol; P < 0.05). LP concentrations were higher in OM than in YM (49 +/- 38 vs. 16 +/- 8 mmol/mol; P < 0.01), and pentosidine concentrations were higher in OM than in YM (73 +/- 13 vs. 11 +/- 2 mmol/mol; P < 0.01). These cross-sectional data raise the possibility that age may not appreciably influence the dimensions or mechanical properties of the human patellar tendon in vivo. Collagen concentration was reduced, whereas both enzymatic and nonenzymatic cross-linking of concentration was elevated in OM vs. in YM, which may be a mechanism to maintain the mechanical properties of tendon with aging.

Fibril Morphology and Tendon Mechanical Properties in Patellar Tendinopathy Effects of Heavy Slow Resistance Training

Background Patellar tendinopathy is characterized by pathologic abnormalities. Heavy slow resistance training (HSR) is effective in the management of patellar tendinopathy, but the underlying functional mechanisms remain elusive. Purpose To investigate fibril morphology and mechanical properties in patellar tendinopathy and the effect of HSR on these properties. Study Design Cohort study; Level of evidence, 2. Methods Eight male patients with patellar tendinopathy completed 12 weeks of HSR. Nine healthy subjects served as controls. Assessments were conducted at baseline and at 12 weeks. Patients assessed symptoms/function and maximal tendon pain during activity. Tendon biopsy samples were analyzed for fibril density, volume fraction, and mean fibril area. Tendon mechanical properties were assessed using force and ultrasonography samplings. Results Patients improved in symptoms/function (P = .02) and maximal tendon pain during activity (P = .008). Stiffness and modulus of control and tendinopathy tendons were similar at baseline. Stiffness remained unaffected in control tendons (3487 ± 392 to 3157 ± 327 N/mm, P = .57) but declined in tendinopathic tendons at 12 weeks (3185 ± 187 to 2701 ± 201 N/mm, P = .04). At baseline, fibril volume fraction was equal, fibril density smaller (P = .03), and mean fibril area tended to be higher in tendinopathy versus controls (P = .07). Fibril morphology remained unchanged in controls but fibril density increased (70% ± 18%, P = .02) and fibril mean area decreased (—26% ± 21%, P = .04) in tendinopathic tendons after HSR. Conclusion Fibril morphology is abnormal in tendinopathy, but tendon mechanical properties are not. Clinical improvements after HSR were associated with changes in fibril morphology toward normal fibril density and mean fibril area. Heavy slow resistance training improved the clinical outcome of patellar tendinopathy, and these improvements were associated with normalization of fibril morphology, most likely due to a production of new fibrils.

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

The knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n = 10) or habitual users of oral estradiol replacement therapy (ERT, n = 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH(2)-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users (P < 0.001), whereas no group difference was seen in tendon NH(2)-terminal propeptide of type I collagen synthesis (P = 0.32). In ERT users, positive correlations between serum estradiol (s-estradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users (P < 0.05), whereas the percentage of large fibrils tended to be greater in control (P = 0.10). A lower Youngs modulus (GPa/%) was found in ERT users (P < 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue.

Dermatan Sulfate Epimerase 1-Deficient Mice have Reduced Content and Changed Distribution of Iduronic acids in Dermatan Sulfate and an Altered Collagen Structure in Skin.

ABSTRACT Dermatan sulfate epimerase 1 (DS-epi1) and DS-epi2 convert glucuronic acid to iduronic acid in chondroitin/dermatan sulfate biosynthesis. Here we report on the generation of DS-epi1-null mice and the resulting alterations in the chondroitin/dermatan polysaccharide chains. The numbers of long blocks of adjacent iduronic acids are greatly decreased in skin decorin and biglycan chondroitin/dermatan sulfate, along with a parallel decrease in iduronic-2-O-sulfated-galactosamine-4-O-sulfated structures. Both iduronic acid blocks and iduronic acids surrounded by glucuronic acids are also decreased in versican-derived chains. DS-epi1-deficient mice are smaller than their wild-type littermates but otherwise have no gross macroscopic alterations. The lack of DS-epi1 affects the chondroitin/dermatan sulfate in many proteoglycans, and the consequences for skin collagen structure were initially analyzed. We found that the skin collagen architecture was altered, and electron microscopy showed that the DS-epi1-null fibrils have a larger diameter than the wild-type fibrils. The altered chondroitin/dermatan sulfate chains carried by decorin in skin are likely to affect collagen fibril formation and reduce the tensile strength of DS-epi1-null skin.

Heavy Slow Resistance Versus Eccentric Training as Treatment for Achilles Tendinopathy: A Randomized Controlled Trial.

Background: Previous studies have shown that eccentric training has a positive effect on Achilles tendinopathy, but few randomized controlled trials have compared it with other loading-based treatment regimens. Purpose: To evaluate the effectiveness of eccentric training (ECC) and heavy slow resistance training (HSR) among patients with midportion Achilles tendinopathy. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 58 patients with chronic (>3 months) midportion Achilles tendinopathy were randomized to ECC or HSR for 12 weeks. Function and symptoms (Victorian Institute of Sports Assessment–Achilles), tendon pain during activity (visual analog scale), tendon swelling, tendon neovascularization, and treatment satisfaction were assessed at 0 and 12 weeks and at the 52-week follow-up. Analyses were performed on an intention-to-treat basis. Results: Both groups showed significant (P < .0001) improvements in Victorian Institute of Sports Assessment–Achilles and visual analog scale from 0 to 12 weeks, and these improvements were maintained at the 52-week follow-up. Concomitant with the clinical improvement, there was a significant reduction in tendon thickness and neovascularization. None of these robust clinical and structural improvements differed between the ECC and HSR groups. However, patient satisfaction tended to be greater after 12 weeks with HSR (100%) than with ECC (80%; P = .052) but not after 52 weeks (HSR, 96%; ECC, 76%; P = .10), and the mean training session compliance rate was 78% in the ECC group and 92% in the HSR group, with a significant difference between groups (P < .005). Conclusion: The results of this study show that both traditional ECC and HSR yield positive, equally good, lasting clinical results in patients with Achilles tendinopathy and that the latter tends to be associated with greater patient satisfaction after 12 weeks but not after 52 weeks.

Mechanical properties of the human Achilles tendon, in vivo

BACKGROUND Ultrasonography has been widely applied for in vivo measurements of tendon mechanical properties. Assessments of human Achilles tendon mechanical properties have received great interest. Achilles tendon injuries predominantly occur in the tendon region between the Achilles-soleus myotendinous junction and Achilles-calcaneus osteotendinous junction i.e. in the free Achilles tendon. However, there has been no adequate ultrasound based method for quantifying the mechanical properties of the free human Achilles tendon. This study aimed to: 1) examine the mechanical properties of the free human Achilles tendon in vivo by the use of ultrasonography and 2) assess the between-day reproducibility of these measurements. METHODS Ten male subjects had the Achilles tendon moment arm length, Achilles tendon cross sectional area and free Achilles tendon length determined. All subjects performed isometric plantarflexion ramp contractions to assess between-day reproducibility on two separate days. Simultaneous ultrasonography based measurements of Achilles-soleus myotendinous junction and Achilles-calcaneus osteotendinous junction displacement together with Achilles tendon force estimates yielded free Achilles tendon mechanical properties. FINDINGS Free Achilles tendon maximal force, deformation and stiffness were 1924 (SD 229) N, 2.2 (SD 0.6) mm and 2622 (SD 534) N/mm on day 1. For between-day reproducibility there were no significant differences between days for free Achilles tendon mechanical properties. The between-day correlation coefficient and typical error percent were 0.81 and 5.3% for maximal Achilles tendon force, 0.85 and 11.8% for maximal Achilles tendon deformation and 0.84 and 8.8% for Achilles tendon stiffness respectively. Last, osteotendinous junction proximal displacement on average contributed with 71 (SD 12) % of proximal myotendinous junction displacement. INTERPRETATION This study, for the first time, presents an ultrasonography based in vivo method for measurement of free AT mechanical properties. The method is applicable for evaluation of free human Achilles tendon mechanical properties in relation to training, injury and rehabilitation.

Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes

Overuse Achilles tendinopathy is a common and challenging problem in sports medicine. Little is known about the etiology of this disorder, and the development of a good animal model for overuse tendinopathy is essential for advancing insight into the disease mechanisms. Our aim was to test a previously proposed rat model for Achilles tendon overuse. Ten adult male Sprague-Dawley rats ran on a treadmill with 10° incline, 1 h/day, 5 days/wk (17-20 m/min) for 12 wk and were compared with 12 control rats. Histological, mechanical, and gene-expression changes were measured on the Achilles tendons after the intervention, and local tendon glucose-uptake was measured before and after the intervention with positron emission tomography. No differences were detected between runners and controls in tissue histology or in glucose uptake, indicating that tendon pathology was not induced. Greater tendon tissue modulus (P < 0.005) and failure stress/body weight (P < 0.02) in runners compared with controls further supported that tendons successfully adapted to uphill running. Several genes of interest were regulated after 12 wk of running. Expression of collagen III and insulin-like growth factor I was increased, while collagen I was unchanged, and decreases were seen in noncollagen matrix components (fibromodulin and biglycan), matrix degrading enzymes, transforming growth factor-β1, and connective tissue growth factor. In conclusion, the tested model could not be validated as a model for Achilles tendinopathy, as the rats were able to adapt to 12 wk of uphill running without any signs of tendinopathy. Improved mechanical properties were observed, as well as changes in gene-expression that were distinctly different from what is seen in tendinopathy and in response to short-term tendon loading.