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© 2012 Human Kinetics - IJATT 17(3), pp. 37-40

Facilitation of Tendon HealingTendinopathy is among the most prevalent musculoskeletal pathologies. Pain, swelling, and impaired performance frequently persist, because the etiology of tendinopathy remains unclear and treatments are often ineffective. The therapeutic benefits of pharmaceuticals are limited to reduction of inflammation and pain.1,2 Consequently, patients often seek

further treatment from athletic trainers and therapists. Rehabilita-tion is often successful for resolution of symp-toms associated with tendinopathy, but the mechanisms underlying therapeutic effects are not well understood.

Tendon repair in-volves a complex inter-action of many factors, including enzymes that

degrade collagen, free radicals, and transcrip-tion factors.3 Figure 1 depicts relationships among factors that play roles in tendon repair, including hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), nitric oxide synthases (NOS), nitric oxide (NO), transforming growth-factor beta 1 (TGF-β1), and matrix metalloproteases (MMPs).3 This report reviews therapeutic

Jennifer Medina McKeon, PhD, ATC, Report Editor

Physiologic Rationale for Selection of Tendinopathy Treatments

THERAPEUTIC MODALITIES

Francisco Molina, PhD; Alma Rus, PhD; Rafael Lomas-Vega, PhD; and Ma Luisa del Moral, MD • University of Jaén, Spain

options that can modulate gene expression and modify protein levels in a manner that facilitates tendon healing. Because relevant research evidence is scarce and controver-sial, this review is focused on the physiologic effects presented in Table 1.3

Thermotherapy and CryotherapyThermotherapy and cryotherapy are com-monly used to treat tendinopathies, but there is conflicting evidence about the effects of these agents. Superficial thermotherapy is reported to facilitate tendon repair. Blood volume and oxygen (O2) saturation have been reported to increase in Achilles tendon during treatment with superficial heat. Furthermore, O2 saturation did not return to pretreatment levels during a 30-minute recovery period after removal of superficial heat.4 On the other hand, superficial heat increases VEGF expression in damaged tendons, which is a marker of increased angiogenesis (i.e., for-mation of new blood vessels). High angiogen-esis rates during the latter stages of tendon repair are detrimental, because the tendon´s ability to resist tension may be reduced.

Cold application has also been found to have contradictory effects on tendon healing. Cryotherapy can increase VEGF expression, thereby promoting angiogenesis, which is harmful during the latter stages of tendon repair. On the other hand, beneficial effects

Tendon repair involves many factors, including enzymes that degrade collagen, free radicals, and transcription factors.

Eccentric training may be effective in acti-vating factors that promote tendon healing.

Shock-wave therapy may be effective in activating factors that promote tendon healing.

Key PointsKey Points

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of cold on injured tendon have also been identified. Specifically, cryotherapy reduces production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are free radicals that can damage the tendon. In addition, cold has been demonstrated to improve regeneration of injured tissue and to reduce musculoskeletal pain.5 Cryotherapy applied with tissue

compression assists venous return and maintenance of elevated O2 levels.6 Consequently, cryotherapy may prevent O2 deficiency within the tendon, which is closely associated with tendinopathy. Cryotherapy may be effective in preventing development of tendi-nopathy, but may be less suitable as a treatment for facilitation of tendon healing.

Figure 1 molecular mechanisms associated with tendon repair. oxygen deficiency activates expression of a hypoxia-inducible factor 1 (hif-1), which activates the liberation of vascular endothelial grow factor (Vegf), transforming growth factor beta 1 (tgf-β1), and nitric oxide synthases (noS)). noS mediates production of the vasodilator nitric oxide (no). the respective effects of Vegf and noS produce angiogenesis and vasodilation, which increases blood perfusion and enhances oxygen delivery. on the other hand, hif-1 and peroxynitrite (onoo), formed by the reaction of no and the free radical superoxide, increase the activity of matrix metalloproteases (mmps), enzymes that degrade the extracellular matrix (ecm) during the first stage of the angiogenesis process. tgf-β1 regulates Vegf activity and can modify collagen deposition or destruction through modulation of expression of mmps. tendinopathy can result from impaired regulation of this complex system.

Table 1. Physiologic Effects of Therapeutic Interventions on Tendon Repair-Related Factors

VEGF ROS NOS TGF-β1 MMPs CollagenThermo-cryotherapy ↑ ↓

Eccentric Training ↑ ↑ ↑ ↑ ↑ ↑

Ultrasound therapy ↑ ↑ ↑ ↑

Shock wave therapy ↑ ↑ ↑ ↑ ↓ ↑

Electrostimulation/Electroacupuncture ↑ ↑Vascular endothelial growth factor (VEGF), reactive oxygen species (ROS), nitric oxide synthases (NOS), transforming growth factor beta 1 (TGF-β1), matrix metal-loproteases (MMPs).

↑ (to increase activity and/or expression); ↓ (to decrease activity and/or expression)

international journal of athletic therapy & training may 2012 39

Eccentric TrainingEccentric training is commonly used for management of tendinopathies, which can reduce pain. However, the location and type of the tendinopathy, as well as the stage of healing, can greatly influence the effectiveness of eccentric exercise. Eccentric training can reduce pain and increase function in patients with chronic Achilles tendinopathy, which may improve tendon circulation. The mechanisms underlying the therapeutic benefits of eccentric training are not well understood, but may be related to the mechano-transduction, which is the physiologic process by which cells sense and respond to mechanical stimuli. Tensile loading may act as a stimulus for tissue repair and remodelling within the tendon.

Eccentric training increases VEGF and TGF-β1 expression in human skeletal muscle, which promotes angiogenesis. Therefore, initiation of eccentric exercise immediately after tendon injury may promote repair by increasing vascularity.7 However, excessive tissue vascularization could result in a prolonged inflamma-tory response.7 Eccentric training has been shown to produce contradictory effects in the vastus lateralis muscle of rats,8 i.e., an increase in both ROS production and NOS expression were found. ROS can damage the tendon, whereas NOS promote vasodilation that could improve tendon healing.

Expression of MMPs, which degrade the extracel-lular matrix (ECM), has been shown to increase within muscle tissue as a result of eccentric training. Increase in expression of MMPs is greatest within tendons as a result of concentric exercise. In addition, eccentric training produces a greater increase in collagen pro-duction within tendons than concentric training. Thus, concentric training program is not recommended for facilitation of tendon healing.

Electrostimulation and Electroacupuncture

Electrostimulation (ES) and electroacupuncture (EA) have been used for treatment of tendinopathy. These modalities have been reported to promote healing through mechanisms related to angiogenesis, vasodi-lation, and remodelling of tendon connective tissue. Jensen et al.9 reported that ES can enhance VEGF expression in muscle cells. They stimulated cells in an incubator for 2 hours at 2 V and a frequency of 50 Hz.

The stimuli consisted of 0.5-second impulse trains with 0.5-second pauses between trains, and 1 millisecond pulse width. Such an effect would be most beneficial during the early stage of tendon healing. Transcutane-ous electrical nerve stimulation (TENS), administered for 30 minutes, 5 times per week over a period of 3 weeks (100 Hz, 15 mA), has been reported to improve the function and quality of life of patients with rotator cuff tendinitis.10 EA has been reported to increase NO liberation from the endothelium of the vastus medialis muscle, which promotes vasodilation.

Ultrasound Therapy

Ultrasound (US) has been shown to be effective in pro-moting tendon healing at a frequency 3 MHz (pulsed delivery; 2 ms on and 8 ms off) and an intensity level of 0.5 W/cm2. US has been shown to elevate TGF-ß1 and VEGF in the tendon, promote fibroblast proliferation and collagen synthesis, and enhance NO level.11 Low-intensity pulsed ultrasound (LIPUS) is most commonly used for promotion of tendon healing. LIPUS has been reported to promote restoration of mechanical strength and collagen alignment in injured patellar tendon when administered during the early stage of healing stages, but it may disturb remodelling and result in a poor collagen fiber alignment when administered during a late stage of healing.12

Shock-Wave Therapy

Shock-wave (SW) therapy has been reported to be more effective for resolution of calcific tendinopathies than a non-calcific condition. The mechanism underlying this differential effect is unknown, but it could relate to mechano-transduction. SW treatment has been reported to increase angiogenesis. Wang et al.13 dem-onstrated that osteoblasts respond to SW therapy with elevated intracellular angiogenic signal transduction, as well as increased expression of VEGF. SW therapy has also been shown to increases collagen synthesis and collagen cross-link formation during the early stage of the healing process in patients with patellar tendinopathy.14 Furthermore, MMPs and inflamma-tory biomarkers have been reported to be significantly decreased in diseased tenocytes after SW treatment.15 A low level of MMPs prevents ECM degradation and improves the mechanical strength of the tendon.

40 may 2012 international journal of athletic therapy & training

SW treatment enhances expression of TGF-β1, collagen type I, and collagen type III in cultivated fibroblasts, suggesting that SW increases fibroblast proliferation through activation of TGF-β1, which necessary to repair the damaged tendon. SW therapy has also been shown to induce collagen remodelling in cellulite-affected human skin. SW has been shown to enhance vasodilation by increasing NO synthesis in femoral artery of ischemic rabbits, which benefits tendon repair.

ConclusionsTendon repair involves numerous factors, including proteins, free radicals, and transcription factors, which interact in a precise sequence to produce specific changes within the tendon structure. Therapeutic procedures that promote resolution of tendinopathies undoubtedly modulate the expression and activity of these tendon repair-related factors. The existing research evidence suggests that eccentric exercise and shock-wave therapy offer the most promising means to promote tendon-repair mechanisms.

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6. Knobloch K, Grasemann R, Spies M, et al. Midportion achilles tendon microcirculation after intermittent combined cryotherapy and com-pression compared with cryotherapy alone: a randomized trial. Am J Sports Med. 2008 Nov;36(11):2128-38.

7. Nakamura K, Kitaoka K, Tomita K. Effect of eccentric exercise on the healing process of injured patellar tendon in rats. J Orthop Sci. 2008 Jul; 13(4):371-8.

8. Lima-Cabello E, Cuevas MJ, Garatachea N, et al. Eccentric exer-cise induces nitric oxide synthase expression through nuclear factor-kappaB modulation in rat skeletal muscle. J Appl Physiol. 2010 Mar;108(3):575-83.

9. Jensen L, Schjerling P, Hellsten Y. Regulation of VEGF and bFGF mRNA expression and other proliferative compounds in skeletal muscle cells. Angiogenesis. 2004; 7(3):255-67.

10. Eyigor C, Eyigor S, Kivilcim Korkmaz O. Are intra-articular corticoste-roid injections better than conventional TENS in treatment of rotator cuff tendinitis in the short run? A randomized study. Eur J Phys Rehabil Med. 2010 Sep;46(3):315-24.

11. Wang FS, Kuo YR, Wang CJ, et al. Nitric oxide mediates ultrasound-induced hypoxia-inducible factor-1alpha activation and vascular endothelial growth factor-A expression in human osteoblasts. Bone. 2004 Jul; 35(1):114-23.

12. Fu SC, Shum WT, Hung LK, Wong MW, Qin L, Chan KM. Low-intensity pulsed ultrasound on tendon healing: a study of the effect of treat-ment duration and treatment initiation. Am J Sports Med. 2008 Sep;36(9):1742-9.

13. Wang FS, Wang CJ, Chen YJ, et al. Ras induction of superoxide acti-vates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. J Biol Chem. 2004 Mar 12;279(11):10331-7.

14. Hsu RW, Hsu WH, Tai CL, Lee KF. Effect of shock-wave therapy on patel-lar tendinopathy in a rabbit model. J Orthop Res. 2004 Jan;22(1):221-7.

15. Han SH, Lee JW, Guyton GP, et al. Effect of extracorporeal shock wave therapy on cultured tenocytes. Foot Ankle Int. 2009 Feb;30(2):93-8.

Francisco Molina is a lecturer at the University of Jaén (Spain) in the Department of Health Sciences.

Alma Rus is a researcher at the University of Jaén (Spain) in the Depart-ment of Experimental Biology.

Rafael Lomas-Vega is a lecturer at the University of Jaén (Spain) in the Department of Health Sciences.

Ma Luisa del Moral is a lecturer at the University of Jaén (Spain) in the Department of Experimental Biology.