Extracorporeal shockwave therapy was initially used for kidney stone disintegration and its application was then extended to calcific tendinitis. The therapeutic field expanded and included numerous types of tendinopathies, from shoulder to plantar fascia. The clinical benefits were documented in trials and the effects and mechanisms were studied on models including animal and human tendons. The present systematic review outlines a large spectrum of biological effects. First, an optimal dose is adapted for each species and each tendon; exceeding the optimal dose may lead to structural injury. Furthermore, the biological effects may be grouped into neovascularization induction, cellularity and extracellular matrix changes, metalloprotease and cytokine modulation, as well as lubricin production. As a result, the remodeled tendon displays improved biomechanical properties to resist stress.
Extracorporeal shock wave therapy (ESWT) was first used for kidney stones, as a method to disintegrate them (
Basically, there are two types of ESWT: Focused and radial shockwave therapy. Focused ESWT is extensively used in clinical practice; it comprises high-energy pressure pulses that converge to a focal point, where maximal pressure is reached. They have an initial high positive pressure wave (up to 80 MPa) with a rapid raise time (30-120 nsec), followed by a negative wave (5-10 MPa). The pulse duration is short, 5 µsec (
Energy flux density (EFD) determines the energy flow through an area perpendicular to the direction of wave propagation and its units are mJ/mm2. The classification of ESWT includes low (<0.08 mJ/mm2), medium (<0.28 mJ/mm2) and high (<0.60 mJ/mm2) EFD (
Microscopically, tendons are composed of cells, tenocytes and extracellular matrix (ECM) that contains collagen, elastin and ground substance. Tenocytes, spindle-shaped cells, are responsible for matrix maintenance and repair and occupy 5% of the tissue volume. ECM contains mainly type I collagen, while type III collagen is the next-most abundant and critical in pathologic tendons and tendon-healing processes (
Tenocytes may convert mechanical stimulation into a biochemical response, leading to the release of growth factors and cellular adaptation (
The therapeutic field of ESWT is continuously expanding, as research adds new opportunities. Post-stroke spasticity was addressed with comparable efficacity with botulinum toxin and both types of ESWT, with the radial form providing the best short- and medium-term results (
A comprehensive literature search was performed in the online databases PubMed (
A total of two authors (DP, DC) independently identified 7,120 titles that were manually checked to exclude reviews and clinical trials and to retain only
Data regarding the optimal dose were analyzed in an attempt to obtain information regarding the following points: Optimal dose for achieving the maximum biologic effect, possible consequences of failing to apply the optimal dose and factors that influence the optimal dose. Furthermore, the investigation was focused on biological effects of ESWT on angiogenesis, cellularity, ECM and biomechanical properties of the tendons.
A summary of the studies (n=23) and their key features/findings is provided in
As for the ECM, in an
Corroborating the results of the published papers, it may be concluded that there is a variability of optimal doses between
Achilles tendinopathy (rabbit) displayed new capillaries in the peritendinous tissue together with larger blood vessels, including differentiated arterioles and venules, at 4 weeks after 2-weekly sessions of 0.29 mJ/mm2, 1,500 pulses (
In normal human cell cultures, ESWT induced a strong and significant release of TGF-β and VEGF, with a maximum at day 2 and persistence of higher levels at day 7. VEGF is stimulated by the release of certain cytokines (IL-6 and IL-10) and is an important promotor of neo-angiogenesis, contributing to the healing process (
In the
Tenocyte metabolism is accelerated with intense production of growth factors (TGF-β1 and IGF-1) involved in ECM biosynthesis. Tenocytes displayed an increased number of nuclei and were actively producing ECM (
One session of ESWT increased the proliferation of either healthy or ruptured tendon-derived human cultured cells, with a more prominent effect on the ruptured tendon-derived cells (a ratio of 1.75). ESWT induced a migratory phenotype in both types of culture, particularly evident for cells derived from ruptured tendons, triggering cell mobility (
Tissue regeneration requires maintenance of the cell phenotype. Phenotyping drift, a natural tendency in cultured rabbit and avian tenocytes, has also been demonstrated in human Achilles tendon cultures, as a tendency to shift from an elongated shape toward an ovoid shape. The phenomenon may be responsible for altered protein synthesis
The cellular compartment of the human tendon includes, besides tenocytes, a population of stem cells, human tendon-derived stem/progenitor cells (hTSPCs), characterized by several phenotypes and a potential for multilineage differentiation (osteoblasts, adipocytes, chondrocytes, tenocytes) (
Tendon regeneration is based on collagen synthesis, initially in the form of type III, followed by a maturation process and transformation in type I. Type I collagen appears like well organized, banded fibrils and provides high tensile strength. Type III collagen takes a woven pattern. Hydroxyproline is an aminoacid component of collagens accounting for ~13% and represents a reliable index for newly formed collagen. Pyridinoline is a crosslink residue of collagen and reflects its rate of degradation.
In the cut and sutured tendon model (rats), ESWT increased the hydroxyproline content, i.e., collagen synthesis, from 2- to 3-fold at days 3 and 9 compared to the control (
In the model of collagenase-induced tendinopathy (rats), the optimal dose of ESWT reversed the increased concentrations of DNA, GAG and hydroxyproline to normal. Fiber bundles displayed a regular arrangement at 12 weeks. Higher doses elicited inhibitory effects on biochemical characteristics and an irregular array of fiber bundles (
At the nanostructural level, ESWT increased the collagen fibril diameter and the fibrillary adhesion force, accelerating healing (
It was postulated that excreted MMPs and cytokines, particularly interleukins, from diseased tenocytes are breaking the ECM and induce tendon damage. Decreasing levels of these substances may reflect healing. Increased excretion of IL-6 and MMP-1, MMP-2 and MMP-13 was found in diseased cultured tenocytes; ESWT application reduced the higher levels of MMP-1, MMP-13 and IL-6 at 72 h, possibly contributing to a metabolic normalization. In normal cultured human tenocytes, only IL-1 levels were increased after ESWT, an event that necessitates further research (
Analysis of the microdialysate from the peritendinous space of human normal and tendinopathic patellar and Achilles tendons revealed that tendinopathy was associated with high levels of IL-6 and IL-8. ESWT application was followed by an increase of these two interleukins, in both normal and diseased tendons within the interval from 1 to 4 h. IL-β1 and IL-2 variations were not significant pre- and post-treatment. Pro-MMP-9, a latent form, increased after ESWT, without any change in the active form levels. The lack of significance of MMP activity changes raised the possibility of grouping individuals as responders and non-responders, with a proportion of responders of 60% in the general population (defined as exhibiting a minimum 5-fold increase in any MMP level at any point post-ESWT) (
The large spectrum of results of the two papers on IL and MMP levels deserves further investigation.
ESWT, a method derived from urinary lithotripsy, represents a new therapeutic approach for tendon pathology, with encouraging results on pain and function. The biological mechanisms that sustain its clinical results have been extensively studied both
Research from the last 20 years indicated that there is a certain optimal dose for the maximum therapeutic effect for each studied species and for each studied tendon. Tendon- and species-specificity is a trait of the therapy. Energies that exceed the optimal value reduce cell viability and disorganize the ECM in a dose-dependent manner, with deleterious consequences on tendon structure.
Scientific papers agreed on several structural alterations that promote tendon healing. ESWT induces neovascularization in the tendinopathic tissue, with extensive capillary formation from the peritendinous structures. The inflammatory reaction that followed the collagenase-induced tendinopathy was accelerated by ESWT.
The therapy acts on both cellular and extracellular compartments of the tendon structure. Tenocyte proliferation and activation as blast-like forms with enhanced protein synthesis together with accelerated mobility reconstruct the normal structure. Accelerated collagen turnover, with type III collagen synthesis and subsequent type I collagen maturation, was documented in the ECM. As a result, biomechanical properties of the treated tendons improved significantly in comparison with non-treated tendinopathic structures. The mechanisms are outlined in
An important clinical effect on plantar fasciitis, a structure that may be assimilated to a tendon, is worth mentioning. Biological studies on plantar fascia are currently lacking; the analgesic effect of ESWT is comparable to that of autologous blood-derived products in the medium-term (6 months). Among the forms of ESWT, the success rate is higher with medium- and high-intensity ESWT (
Future research will focus on the role of cytokines and metalloproteases that mediate, at a cellular level, the degenerative process and its evolution under ESWT application.
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Conceptualization: DP; methodology: DP and DC; resources: MIS and DC; writing and draft preparation: DP, MIS and DC. All authors have read and agreed to the published version of the manuscript. Data authentication is not applicable.
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The authors declare that they have no competing interests.
Flowchart of study selection. ESWT, extracorporeal shock wave therapy.
Main biological effects of ESWT application on tendon. ESWT, extracorporeal shock wave therapy; eNOS, endothelial nitric oxide synthase; PCNA, proliferating cell nuclear antigen; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-β; NO, nitric oxide; IGF-1, insulin-like growth factor 1; ECM, extracellular matrix.
Studies on biological effects of ESWT on human and animal tendons.
Author, year | Studied tissue/organism | ESWT doses, sessions | Study time-points | Optimal dose | Neoangiogenesis | Cellularity | ECM | Mechanical properties | (Refs.) |
---|---|---|---|---|---|---|---|---|---|
Rompe, 1998 | 42 rabbits, normal Achilles tendon, |
One session, 1,000 pulses, 0.08, 0.28 and 0.60 mJ/mm2 | 1, 7, 14 and 28 days after | 0.08 and 0.28 mJ/mm2 caused no damage; with 0.60 mJ/mm2, fibrinoid necrosis, inflammation and reparative peritendinous reactions occurred | N/A | N/A | N/A | N/A | ( |
Orhan, 2001 | 48 rats, cut and sutured Achilles tendon, |
One session 500 shocks, 0.12 mJ/mm2 | 2 and 3 weeks | N/A | N/A | Week 2: Intense inflammatory reaction;week 3: Improved, organized healing | Increased hydroxyproline formation (days 3 and 9) | N/A | ( |
Wang, 2002 | 8 dogs, normal Achilles tendon-bone junction, |
One session, 0.18 mJ/mm2, 1,000 pulses | Before treatment and at 4 and 8 weeks after | N/A | New capillaries at 4 weeks (17-fold increase) and at 8 weeks (16-fold); muscularized vessels at 4 and 8 weeks | N/A | N/A | N/A | ( |
Maier, 2002 | 36 rabbits, normal quadriceps tendon, |
1,500 pulses at 0.35, 0.5, 0.9 or 1.2 mJ/mm2 | 10 and 28 days | 0.35 mJ/mm2: No histologic alteration at 10 days 0.5 and 0.9 mJ/mm2: Minimal edema in the paratenon that disappeared at 28 days; 1.2 mJ/mm2: Modified tendon structure at 10 days | N/A | N/A | N/A | N/A | ( |
Wang, 2003 | 50 rabbits, normal Achilles tendon, |
One session 500 shocks, 0.12 mJ/mm2 | 24 h; 1, 4, 8 and 12 weeks | N/A | Neovascularization increased at 4 weeks, persisting at 12 weeks (eNOS, VEGF, PCNA) | N/A | N/A | N/A | ( |
Chen, 2004 | 48 rats, collagenase-induced Achilles tendinosis, |
One session, 200 shocks, 0.16 mJ/mm2 | 1, 2, 4, 6 and 12 weeks after session | N/A | N/A | Tenocyte proliferation (PCNA); tenocyte stimulation (TGF-β1, IGF-1) | N/A | Restauration of mechanical load-to-failure and stiffness of healing tendons | ( |
Hsu, 2004 | 18 rabbits, Collagenase-induced patellar tendinopathy, |
Two weekly sessions, 1,500 pulses, 0.29 mJ/mm2 | 4 and 16 weeks after treatment | N/A | 4 weeks: New capillaries in the peritendinous tissue, larger blood vessels, differentiated arterioles and venules | 4 weeks: Tenocyte stimulation; 16 weeks: Increased healing process | Higher HP levels at weeks 4 and 16; higher pyridinoline levels (up to 10 times at 4 weeks) | 4 and 16 weeks: Higher ultimate tensile load than control that increased from 4 to 16 weeks | ( |
Orhan, 2004 | 32 rats, normal Achilles tendon, |
One session of 1,000 pulses at 0.15 mJ/mm2, 1,500 pulses at 0.15 mJ/mm2, 2,000 pulses at 0.20 mJ/mm2 | 3 weeks | 0.15 mJ/mm2, at 1,000 and 1,500 pulses, no alteration of structure 0.20 mJ/mm2 and 2,000 pulses: Alteration of tendon structure | N/A | N/A | N/A | N/A | ( |
Orhan, 2004 | 48 rats, ruptured Achilles tendon, |
One session 500 pulses, 0.19 mJ/mm2 | 20 days | N/A | Increased number of capillaries | N/A | Absent or minimal adhesions that did not distort the configuration of the tendon | The mean force required to rupture the tendon was higher | ( |
Kersh, 2006 | 6 horses, collagenase-induced tendinosis of superficial digital flexor tendon, |
3 sessions, 1,500 shocks, 0.14 mJ/mm2 (3 weeks interval between sessions) | 5 weeks after completion | N/A | Neovascularization (significantly more capillaries); increased metachromasia within the intima and subintima of larger arteries | Increased number of fibroblasts (not significant); increase in the number of tenocyte nuclei; tenocytes were actively producing ECM | N/A | N/A | ( |
Bosch, 2007 | 6 ponies, normal superficial flexor tendon; normal common digital extensor tendon, |
Focused session ESWT, 600 shocks, 0.14 mJ/mm2 | After 3 h and 6 weeks | N/A | N/A | At 3 h: Higher synthesis rate of GAG and collagen; at 6 weeks: Decreased GAG and total collagen | N/A | N/A | ( |
Chao, 2008 | Rats, cultured Achilles tendon normal cells, |
One session of focused ESWT 0.36 or 0.68 mJ/mm2 50, 100, 250 or 500 pulses | 24, 48 and 96 h | Optimal dose: 100 pulses at 0.36 mJ/mm2 that maintained cell viability | N/A | Tenocyte proliferation (PCNA); increased tenocyte synthesis (TGF-β1, IGF-1) | N/A | N/A | ( |
Han, 2009 | Human, cultured Achilles tendinopathy and normal FHL tendon, |
One session 0.17 mJ/mm2, 250, 500, 1,000 or 2,000 pulses | 72 h | Optimal dose for cell viability: 500 pulses; optimal dose for cell proliferation: 500 pulses | N/A | N/A | Normal tenocytes: Increase of IL-1; diseased tenocytes: Decrease of MMP-1, MMP-13 and IL-6 | N/A | ( |
Bosch, 2009 | 6 ponies, normal superficial digital flexor tendon; normal common digital extensor tendon, |
Focused session ESWT, 600 shocks, 0.14 mJ/mm2 | After 3 h and 6 weeks | N/A | N/A | 3 h: Tenocyte activation, structural disorganization | 3 h: Increased collagen cleavage; 6 weeks: No collagen damage | N/A | ( |
Zhang, 2011 | 12 Rats, normal knee tendon, |
2 different doses: 3,000 pulses of 0.15 or 0.4 mJ/mm2 | 4 days | N/A | N/A | N/A | Increased lubricin in tendons, dose-dependent | N/A | ( |
Vetrano, 2011 | Human, cultured normal semitendinosus cells, |
One session 0.08, 0.14 and 0.17 mJ/mm2, 500 and 1,000 pulses | 1, 4, 8 and 12 days | None of the regimens affected viability of cells | N/A | None of the regimens affected viability of cells. 1,000 pulses, 0.14 mJ/mm2 promoted tenocyte proliferation, prevented phenotype drift | Increased collagen synthesis, particularly type I | N/A | ( |
Penteado, 2011 | 30 rabbits, normal patellar tendon, tibial insertion, |
One session, 6 different regimens (0.18, 0.27 or 0.36 mJ/mm2, 1,000 and 2,000 pulses) | 6 weeks | N/A | No difference in blood vessels | N/A | N/A | N/A | ( |
Leone, 2012 | Human, cultured tendinopathic cells from Achilles tendon. Normal semitendinosus tendon, |
One session, 0.14 mJ/mm2, 1,000 pulses | 1 and 4 days | N/A | N/A | ESWT induced no morphological variations (normal and diseased); ESWT induced proliferation of tenocytes (normal and diseased), more in diseased; ESWT induced cell migration in both cultures after trauma, more in diseased (wound repair) | ESWT reduced the increased concentrations of Col I and Scx in diseased cultures | N/A | ( |
Branes, 2012 | Human, 31 rotator cuff tendinopathy (10 treated and 21 controls), |
One session, 0.3 mJ/mm2, 4,000 pulses | After session | N/A | ESWT increased VVA, nodular neo-angiogenesis for grade III in deeper layers, no response for grade IV | N/A | N/A | N/A | ( |
Yoo, 2012 | 45 rats, collagenase-induced Achilles tendinopathy, |
4 sessions, 1,000 pulses, 0.085 mJ/mm2, days 5, 8, 12 and 15 | Days 7, 12, 19, 26 and 33 after baseline | N/A | Day 33: No inflammatory cells or fibrotic tissue | Increase in fibrillary diameter and fibrillary adhesion force | N/A | N/A | ( |
de Girolamo, 2014 | Human, cultured normal tendons, |
One session, 1,000 pulses, 0.17 mJ/mm2 | Days 1, 2, 4 and 7 after treatment | Increased cell viability | N/A | N/A | Increased expression of Scx and type I collagen, increased IL-β1, IL-6 and IL-10 | N/A | ( |
Waugh, 2015 | Human, normal (n=19) and tendinopathic (n=10) tendons, |
One session, 2,500 pulses, 0.064 mJ/mm2 | 1, 2, 3 and 4 h | N/A | N/A | Elevated levels of IL-6 and IL-8 post ESWT remained higher at 4 h; elevated levels of pro-MMP-9, without active form increase | N/A | N/A | ( |
Leone, 2016 | Human, cultured normal semitendinosus and ruptured Achilles, |
One session, 1,000 pulses, 0.14 mJ/mm2 | 21 days | N/A | Increased tenocyte proliferation, migration and collagen synthesis, more intense in ruptured tendons | N/A | N/A | N/A | ( |
eNOS, endothelial nitric oxide synthase; VEGF, vascular endothelial growth factor; PCNA, proliferating cell nuclear antigen; GAG, glycosaminoglycan; HP, hydroxyproline; VVA, vascular volume area; Scx, scleraxis; N/A, information not available; ESWT, extracorporeal shock wave therapy; ECM, extracellular matrix.