A review of the cellular and molecular effects of extracorporeal shockwave therapy

Summary

Extracorporeal shockwave therapy (ESWT) is a novel therapeutic modality and its use in promoting connective tissue repair and analgesic effect has been advocated in the literature. It is convenient, cost-effective, and has negligible complications; it therefore bypasses many of the problems associated with surgical interventions. This paper reviews the proposed mechanisms of action in promoting tissue repair and regeneration as well as analysing its efficacy providing an analgesic effect in clinical applications. Further research will be required to not only identify the underlying mechanisms more precisely, but will also be critical for ensuring consistency across the literature so that the most beneficial treatment protocol can be developed. Extracorporeal shockwave therapy stands as a promising alternative modality in promoting tissue repair.

Keywords

Shockwave - mechanisms - healing

• References

• 1 Gebhart C, Widhalm R. The biological effects of shockwave treatment. In Coombs R, Schaden W, Zhou SSH. editors Musculoskeletal shockwave therapy. London: Greenwich Medical Media Ltd; 2000. pg 11-12
• 2 Wang CJ. Extracorporeal shockwave therapy in musculoskeletal disorders. J Orthop Surg Res 2012; 7: 7-11.
• 3 Thiel M. Application of shock waves in medicine. Clin Orthop Rel Res 2001; 387: 18-21.
• 4 Haupt G, Haupt A, Ekkernkamp A. et al. Influence of shock waves on fracture healing. Urology 1992; 39: 529-532.
• 5 Knobloch K, Vogt PM. High-energy focussed extracorporeal shockwave therapy reduces pain in plantar fibromatosis (Ledderhose's disease). Biomed Central Res Notes 2012; 5: 542.
• 6 Haupt G. Use of extracorporeal shock waves in the treatment of pseudoarthrosis, tendinopathy and other orthopedic diseases. J Urology 1997; 158: 4-11.
• 7 Rompe JD, Zoellner J, Nafe B. Shock wave therapy versus conventional surgery in the treatment of calcifying tendinitis of the shoulder. Clin Orthop Rel Res 2001; 387: 72-82.
• 8 Mouzopoulos G, Stamatakos M, Mouzopoulos D. et al. Extracorporeal shock wave treatment for shoulder calcific tendonitis: a systematic review. Skeletal Radiol 2007; 36: 803-811.
• 9 Pleiner J, Crevenna R, Langenberger H. et al. Extracorporeal shockwave treatment is effective in calcific tendonitis of the shoulder. A randomized controlled trial. Wien Klin Wohenschr 2004; 116: 536-541.
• 10 Peters J, Luboldt W, Schwarz W. et al. Extracorporeal shock wave therapy in calcific tendinitis of the shoulder. Skeletal Radiol 2004; 33: 712-718.
• 11 Carulli C, Tonelli F, Innocenti M. et al. Effectiveness of extracorporeal shockwave therapy in three major tendon diseases. J Orthop Traumatol 2015 Jul 2 [Epub ahead of print]
• 12 Wang CJ, Chen HS. Shock wave therapy for patients with lateral epicondylitis of the elbow: a one- to two-year follow-up study. Am J Sports Med 2002; 30: 422-425.
• 13 Rompe JD, Theis C, Maffulli N. Shock wave treatment for tennis elbow. Orthopade 2005; 34: 567-570.
• 14 Rompe JD, Decking J, Schoellner C. et al. Repetitive low-energy shock wave treatment for chronic lateral epicondylitis in tennis players. Am J Sports Med 2004; 32: 734-743.
• 15 Ozturan KE, Yucel I, Cakici H. et al. Autologous blood and corticosteroid injection and extracoporeal shock wave therapy in the treatment of lateral epicondylitis. Orthopedics 2010; 33: 84-91.
• 16 Radwan YA, El Sobhi G, Badawy WS. et al. Resistant tennis elbow: Shockwave therapy versus percutaneous tenotomy. Int Orthop 2008; 32: 671-677.
• 17 Hsu CJ, Wang DY, Tseng KF. et al. Extracorporeal shock wave therapy for calcifying tendinitis of the shoulder. J Shoulder Elbow Surg 2008; 17: 55-59.
• 18 Wilner JM, Strash WW. Extracorporeal shockwave therapy for plantar fasciitis and other musculoskeletal conditions utilizing the Ossatron: An update. Clin Podi Med Surg 2004; 21: 441-447.
• 19 Rasmussen S, Christensen M, Mathiesen I. et al. Shockwave therapy for chronic Achilles tendinopathy: A double-blind, randomized clinical trial of efficacy. Acta Orthop 2008; 79: 249-256.
• 20 Furia JP. High-energy extracorporeal shock wave therapy as a treatment for chronic insertional Achilles tendinopathy. Am J Sports Med 2006; 34: 733-740.
• 21 Furia JP. High-energy extracorporeal shock wave therapy as a treatment for chronic non-insertional Achilles tendinopathy. Am J Sports Med 2008; 36: 502-508.
• 22 van Leeuwen MT, Zwerver J, van den Akker-Scheek I. Extracorporeal shockwave therapy for patellar tendinopathy: A review of the literature. Br J Sports Med 2009; 43: 163-168.
• 23 Vulpiani MC, Vetrano M, Savoia V. et al. Jumper’s knee treatment with extracorporeal shock wave therapy: a long-term follow-up observational study. J Sports Med Phys Fitness 2007; 47: 323-328.
• 24 Wang CJ, Ko JY, Chan YS. et al. Extracorporeal shockwave for chronic patellar tendinopathy. Am J Sports Med 2007; 35: 972-978.
• 25 Peers KH, Lysens RJ, Brys P. et al. Cross-sectional outcome analysis of athletes with chronic patellar tendinopathy treated surgically and by extracorporeal shock wave therapy. Clin J Sport Med 2003; 13: 79-83.
• 26 Zwerver J, Dekker F, Pepping GJ. Patient-guided piezo-electric extracorporeal shockwave therapy as treatment for chronic severe patellar tendinopathy: A pilot study. J Back Musculoskelet Rehabil 2010; 23: 111-115.
• 27 Ludwig J, Lauber S, Lauber HJ. et al. High-energy shock wave treatment of femoral head necrosis in adults. Clin Orthop Rel Res 2001; 387: 119-126.
• 28 Wang CJ, Wang FS, Huang CC. et al. Treatment for osteonecrosis of the femoral head: comparison of extracorporeal shock waves with core decompression and bone-grafting. J Bone Joint Surg (Am) 2005; 87: 2380-2387.
• 29 Kong FR, Liang YJ, Oin SG. et al. Clinical application of extracorporeal shock wave to repair and reconstruct osseous tissue framework in the treatment of avascular necrosis of the femoral head (ANFH). Zhongguo Gushang 2010; 23: 12-15.
• 30 Alves EM, Angrisani AT, Santiage MB. The use of extracorporeal shock waves in the treatment of osteonecrosis of the femoral head: a systematic review. Clin Rheuma 2009; 28: 1247-1251.
• 31 Wang CJ, Wang FS, Yang KD. et al. Treatment of osteonecrosis of the hip: comparison of extracorporeal shockwave with shockwave and alendronate. Arch Orthop Trauma Surg 2008; 128: 901-908.
• 32 Wang CJ, Wang FS, Ko JY. et al. Extracorporeal shockwave therapy shows regeneration in hip necrosis. Rheumatology 2008; 4: 542-546.
• 33 Cacchio A, Giordano L, Colafarina O. et al. Extracorporeal shockwave therapy compared with surgery for hypertrophic long-bone nonunions. J Bone Joint Surg (Am) 2009; 91: 2589-2597.
• 34 Elster EA, Stojadinovic A, Forsberg J. et al. Extracorporeal shock wave therapy for nonunion of the tibia. J Orthop Trauma 2010; 24: 133-141.
• 35 Schaden W, Fischer A, Sailer A. Extracorporeal shock wave therapy of nonunion or delayed osseous union. Clin Orthop 2001; 387: 90-94.
• 36 Mueller M, Bockstahler B, Skalicky M. et al. Effects of radial shockwave therapy on the limb function of dogs with hip osteoarthritis. Vet Rec 2007; 160: 762-765.
• 37 Dahlberg J, Fitch G, Evans RB. et al. The evaluation of extracorporeal shockwave therapy in naturally occurring osteoarthritis of the stifle joint in dogs. Vet Comp Orthop Traumatol 2005; 18: 147-152.
• 38 Crowe OM, Dyson SJ, Wright IM. et al. Treatment of chronic or recurrent proximal suspensory desmitis using radial pressure wave therapy in the horse. Equine Vet J 2004; 36: 313-316.
• 39 Lischer CJ, Ringer SK, Schnewlin M. et al. Treatment of chronic proximal suspensory desmitis in horses using focused electrohydraulic shockwave therapy. Schweiz Arch fur Tierheilkunde 2006; 148: 561-568.
• 40 Lyon R, Liu XC, Kubin M. et al. Does extracorporeal shock wave therapy enhance healing of osteochondritis dissecans of the rabbit knee? A pilot study. Clin Orthop Rel Res 2013; 471: 1159-1165.
• 41 McClure SR, van Sickle D, Evans R. et al. The effects of extracorporeal shockwave therapy on the ultrasonographic and histologic appearance of collagenase-induced equine forelimb suspensory ligament desmitis. Ultrasound Med Biol 2004; 30: 461-467.
• 42 Kieves NR, Mackay CS, Adducci K. et al. High energy focused shockwave therapy accelerates bone healing. A blinded, prospective, randomised clinical trial. Vet Comp Orthop Traumatol 2015; 28: 425-432.
• 43 Barnes K, Lanz O, Werre S. et al. Comparison of autogenous cancellous bone grafting and extracorporeal shock wave therapy on osteotomy healing in the tibial tuberosity advancement procedure in dogs. Vet Comp Orthop Traumatol 2015; 28: 207-214.
• 44 Souza ANA, Ferreira MP, Hagen SCF. et al. Radial shock wave therapy in dogs with hip osteoarthritis. Vet Comp Orthop traumatol 2016; 29: 108-114.
• 45 McClure S, Dorfmuller C. Extracorporeal shock wave therapy: theory and equipment. Clinical applications and regulation. Clin Tech Equine Prac 2003; 2: 348-357.
• 46 Mariotto S, Carcereri de Prati A, Cavalieri E. et al. Extracorporeal shock wave therapy in inflammatory diseases: Molecular mechanism that triggers anti-inflammatory action. Curr Med Chem 2009; 16: 2366-2372.
• 47 Wang FS, Yang KD, Kuo YR. et al. Temporal and spatial expression of bone morphogenetic proteins in extracorporeal shock wave-promoted healing of segmental defect. Bone 2003; 32: 387-396.
• 48 Wang CJ, Yang KD, Ko JY. et al. The effects of shockwave on bone healing and systemic concentrations of nitric oxide (NO), TGF-B1, VEGF and BMP-2 in long bone non-unions. Nitric Oxide 2009; 20: 298-303.
• 49 Yin TC, Wang CJ, Yang KD. et al. Shockwaves enhance osteogenetic gene expression in marrow stromal cells from hips with osteonecrosis. Chang Gung Med J 2011; 344: 367-374.
• 50 Catalano MG, Marano F, Rinella L. et al. Extracorporeal shockwaves (ESWs) enhance the osteogenic medium-induced differentiation of adipose-derived stem cells into osteoblast-like cells. J Tiss Eng Regen Med 2014 June 1 [Epub ahead of print]
• 51 Wang FS, Wang CJ, Sheen-Chen SM. et al. Superoxide mediates shock wave induction of ERK-dependent osteogenic transcription factor (CBFA1) and mesenchymal cell differentiation toward osteoprogenitors. J Biol Chem 2002; 277: 10931-10937.
• 52 Wang FS, Yang KD, Chen RF. et al. Extracorporeal shock wave promotes growth and differentiation of bone-marrow stromal cells towards osteoprogenitor associated with induction of TGF-beta1. J Bone Jt Surg (Br) 2002; 84: 457-461.
• 53 Wang CJ, Wang FS, Yang KD. Biological effects of extracorporeal shockwave in bone healing: a study in rabbits. Arch Orthop Trauma Surg 2008; 128: 879-884.
• 54 Kong FR, Liang YJ, Qin SG. et al. Clinical application of extracorporeal shock wave to repair and reconstruct osseous tissue framework in the treatment of avascular necrosis of the femoral head. Chin J Orthop Traumatol 2010; 23: 12-15.
• 55 Price JS, Sugiyama T, Galea GL. et al. Role of endocrine and paracrine factors in the adaptation of bone to mechanical loading. Curr Osteopor Res 2011; 9: 76-82.
• 56 Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strains. Calcif Tiss Internat 1995; 57: 344-358.
• 57 Sakai K, Mohtai M, Iwamoto Y. Fluid shear stress increases transforming growth factor beta 1 expression in human osteoblast-like cells: Modulation by cation channel blockades. Calc Tiss Internat 1998; 63: 515-520.
• 58 Salter DM, Wallace WH, Robb JE. et al. Human bone cell hyperpolarisation response to cyclical mechanical strain is mediated by an interleukin-1beta autocrine/paracrine loop. J Bone Min Res 2000; 15: 1746-1755.
• 59 Wang FS, Wang CJ, Huang HJ. et al. Physical shock wave mediates membrane hyperpolarization and Ras activation for osteogenesis in human bone marrow stromal cells. Bioch Biophys Res Commun 2001; 287: 648-655.
• 60 Chen YJ, Kuo YR, Yang KD. et al. Shock wave application enhances pertussis toxin protein-sensitive bone formation of segmental femoral defects in rats. J Bone Min Res 2003; 18: 2169-2179.
• 61 Franceschi RT, Xiao G, Jiang D. et al. Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Conn Tiss Res 2003; 1: 109-116.
• 62 Sun D, Junger WG, Yuan C. et al. Shockwave induces osteogenic differentiation of human mesenchymal stem cells through ATP release and activation of P2X7 receptors. Stem Cells 2013; 31: 1170-1180.
• 63 Chen YJ, Kuo YR, Yang KD. et al. Activation of extracellular signal-related kinase (ERK) and p38 kinase in shock wave-promoted bone formation of segmental defect in rats. Bone 2004; 34: 466-477.
• 64 Seger R, Krebs EG. The MAPK signaling cascade. Fed American Soc Exp Biol 1995; 9: 726-735.
• 65 Jaiswal RK, Jaiswal N, Bruder SP. et al. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem 2000; 275: 9645-9652.
• 66 Deora AA, Hajjar DP, Lander HM. Recruitment and activation of Raf-1 kinase by nitric oxide-activated Ras. Biochem 2000; 39: 9901-9908.
• 67 Lodish H, Berk A, Matsudaira P. et al. Receptor tyrosine kinases and activation of Ras. In Molecular Cell Biology. New York: WH Freeman; 2003. Pg 587-589
• 68 Komori T. Regulation of osteoblast differentiation by Runx2. Adv Exp Med Biol 2000; 658: 43-49.
• 69 Kobayashi H, Gao Y-H, Ueta C. et al. Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro. Biochem Biophys Res Commun 2000; 273: 630-636.
• 70 Stricker S, Fundele R, Vortkamp A. et al. Role of Runx genes in chondrocyte differentiation. Devel Biol 2002; 245: 95-108.
• 71 Xiao G, Jiang D, Thomas P. et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem 2000; 275: 4453-4459.
• 72 Wang FS, Wang CJ, Chen YJ. et al. Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. J Biol Chem 2004; 279: 10331-10337.
• 73 Wang CJ, Huang KE, Sun YC. et al. VEGF modulates angiogenesis and osteogenesis in shockwave-promoted fracture healing in rabbits. J Surg Res 2011; 171: 114-119.
• 74 Zelzer E, Glotzer DJ, Hartmann C. et al. Tissue specific regulation of VEGF expression during bone development required Cbfa1/RUNX2. Mech Devel 2001; 106: 97-106.
• 75 Kwon TG, Zhao X, Yang Q. et al. Physical and functional interactions between Runx2 and HIF-1α induce vascular endothelial growth factor gene expression. J Cell Biochem 2011; 112: 3582-3593.
• 76 Mayer H, Bertram H, Lindenmaier W. et al. Vascular endothelial growth factor (VEGF-A) expression in human mesenchymal stem cells: autocrine and paracrine role on osteoblastic and endothelial differentiation. J Cell Biochem 2005; 95: 827-839.
• 77 Mayr-Wohlfart U, Waltenberger J, Hausser H. et al. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone 2002; 30: 472-477.
• 78 Street J, Bao M, de Guzman L. et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Nat Acad Sci USA 2002; 99: 9656-9661.
• 79 Deckers MML, Karperien M, van der Bent C. et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinol 2000; 141: 1667-1674.
• 80 Peng H, Usas A, Olshanski A. et al. VEGF improves, where sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis. J Bone Min Res 2005; 20: 2017-2027.
• 81 Peng H, Wright V, Usas A. et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 2002; 110: 751-759.
• 82 Deckers MML, van Bezooijen RL, van Geertje Horst DER. et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinol 2002; 143: 1545-1553.
• 83 Wagner DO, Sieber C, Bhushan R. et al. BMPs: from bone to body morphogenetic proteins. Science Signal 2010; 3: mr1.
• 84 Chen G, Deng C, Li YP. TGF-B and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 2012; 8: 272-288.
• 85 von Bubnoff A, Cho KW. Intracellular BMP signaling regulation in vertebrates: Pathway or network?. Devel Biol 2001; 239: 1-14.
• 86 Lai CF, Cheng SL. Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells. J Biol Chem 2002; 277: 15514-15522.
• 87 Lee KS, Hong SH, Bae SC. Both the Smad and p38 MAPK pathway play a crucial role in RUNX2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Oncog 2002; 21: 7156-7163.
• 88 Nishimura R, Hata K, Harris SE. et al. Core-binding factor alpha 1 (Cbfa1) induces osteoblastic differentiation of C2C12 cells without interaction with Smad1 and Smad5. Bone 2002; 31: 303-312.
• 89 Baksh D, Song L, Tuan RS. Adult mesenchymal stem cells: Characterisation, differentiation, and application in cell and gene therapy. J Cell Mol Med 2004; 8: 301-316.
• 90 Barnes GL, Kostenuik PJ, Louis CG. et al. Growth factor regulation of fracture repair. J Bone Min Res 1999; 14: 1805-1815.
• 91 Suzawa M, Takeyuchi Y, Fukumoto S. et al. Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro. Endocrinol 1999; 140: 2125-2133.
• 92 Yamaguchi A, Ishizuya T, Kintou N. et al. Effects of BMP-2, BMP-4 and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochem Biophys Res Commun 1996; 220: 366-371.
• 93 Tsuji K, Bandyopadhyaym A, Harfe BD. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nature Genet 2006; 38: 1424-1429.
• 94 Wang CJ, Yang KD, Wang FS. et al. Shock wave induces neovascularization at the tendon-bone junction. A study in rabbits. J Orthop Res 2003; 21: 984-989.
• 95 Harris SE, Sabatini M, Harris MA. et al. Expression of bone morphogenetic protein messenger RNA in prolonged cultures of fetal rat calvarial cells. J Bone Min Res 1994; 9: 389-394.
• 96 Aspenberg P, Basic N, Tagil M. et al. Reduced expression of BMP-3 due to mechanical loading: a link between mechanical stimuli and tissue differentiation. Acta Orthop Scand 2000; 71: 558-562.
• 97 Daluiski A, Engstrand T, Bahamonde ME. et al. Bone morphogenetic protein-3 is a negative regulator of bone density. Nature Genet 2001; 27: 84-88.
• 98 Hausdorf J, Sievers B, Schmitt-Sody M. et al. Stimulation of bone growth factor synthesis in human osteoblasts and fibroblasts after extracorporeal shock wave application. Arch Orthop Trauma Surg 2011; 131: 303-309.
• 99 Solchaga LA, Penick K, Porter JD. et al. FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells. J Cell Physiol 2005; 203: 398-409.
• 100 Nakamura T, Hara Y, Tagawa M. et al. Recombinant human basic fibroblast growth factor accelerates fracture healing by enhancing callus remodeling in experimental dog tibial fractures. J Bone Min Res 1998; 13: 942-949.
• 101 Xiao G, Jiang D, Gopalakrishnan R. et al. Fibroblast growth factor 2 induction of the osteocalcin gene required MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/RUNX2. J Biol Chem 2002; 277: 36181-36187.
• 102 Hofmann A, Ritz U, Hessmann MH. et al. Extracorporeal shock wave-mediated changed in proliferation, differentiation, and gene expression of human osteoblasts. J Trauma 2008; 65: 1402-1410.
• 103 Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone: bad cop, good cop?. Trends Endocrinol Metabol 2010; 21: 294-301.
• 104 Haversath M, Catelas I, Li X. et al. PGE2 and BMP-2 in bone and cartilage metabolism: Two intertwining pathways. Can J Physiol Pharmacol 2012; 90: 1434-1445.
• 105 Graham S, Gamie Z, Polyzois I. et al. Prostaglandin EP2 and EP4 receptor agonists in bone formation and bone healing: In vivo and in vitro evidence. Exp Opin Investig Drugs 2009; 18: 746-766.
• 106 Boening KJ, Loffeld S, Weitkamp K. et al. Radial extracorporeal shock wave therapy for chronic insertion desmopathy of the proximal suspensory ligament. In: Proceedings of the 46th Annual Convention of the American Association of Equine Practitioners 2000. November 26-29 San Antonio, TX; USA: pg. 203-207
• 107 Revenaugh MS. ESWT for treatment of osteoarthritis in the horse: clinical applications. Vet Clin N Am: Equine Pract 2005; 21: 609-625.
• 108 McClure SR, Sonea IM, Evans RB. et al. Evaluation of analgesia resulting from extracorporeal shock wave therapy and radial pressure wave therapy in the limbs of horses and sheep. Am J Vet Res 2005; 66: 1702-1708.
• 109 Dahlberg JA, McClure SR, Evans RB. et al. Force platform evaluation of lameness severity following extracorporeal shock wave therapy in horses with unilateral forelimb lameness. J Am Vet Med Assoc 2006; 299: 100-103.
• 110 Ochiai N, Ohtori S, Sasho T. et al. Extracorporeal shock wave therapy improves motor dysfunction and pain originating from knee osteoarthritis in rats. Osteoarth Cartil 2007; 15: 1093-1096.
• 111 Ohtori S, Inoue G, Mannoji C. et al. Shock wave application to rat skin induces degeneration and re-innervation of sensory nerve fibres. Neurosci Letters 2001; 315: 57-60.
• 112 Takahashi N, Wada Y, Ohtori S. et al. Application of shock waves to rat skin decreases calcitonin gene-related peptide immunoreactivity in dorsal root ganglion neurons. Autonom Neurosci 2003; 107: 81-84.
• 113 He X, Schepelmann K, Schaible HG. et al. Capsaicin inhibits responses of fine afferents from the knee joint of the cat to mechanical and chemical stimuli. Brain Res 1990; 530: 147-150.
• 114 Takahashi N, Ohtori S, Saisu T. et al. Second application of low-energy shock waves has a cumulative effect on free nerve endings. Clin Orthop Rel Res 2006; 443: 315-319.
• 115 Murata R, Ohtori S, Ochiai N. et al. Extracorporeal shockwaves induce the expression of ATF3 and GAP-43 in rat dorsal root ganglion neurons. Autonom Neurosci 2006; 128: 96-100.
• 116 Hausdorf J, Lemmens MAM, Heck KDW. et al. Selective loss of unmyelinated nerve fibres after extracorporeal shockwave application to the musculoskeletal system. Neurosci 2008; 155: 138-144.
• 117 Bolt DM, Burba DJ, Hubert JD. et al. Determination of functional and morphologic changes in palmar digital nerves after nonfocused extracorporeal shock wave treatment in horses. Am J Vet Res 2004; 65: 1714-1718.
• 118 Rompe JD, Bohl J, Riehle HM. et al. Überprüfung der Läsionsgefahr des N. ischiadicus des Kaninchens durch die Applikation niedrig- und mittelenergetischer extrakorporaler Stoßwellen [Possible damage to the rabbit sciatic nerve by the application of extracorporeal shock waves or low or middle energy flux density]. Z Orthop Unfall 1998; 136: 407-411.
• 119 Haake M, Thon A, Bette M. Absence of spinal response to extracorporeal shock waves on the endogenous opioid systems in the rat. Ultrasound Med Biol 2001; 27: 279-284.
• 120 Haake M, Thon A, Better M. No influence of low-energy extracorporeal shock wave therapy (ESWT) on spinal nociceptive systems. J Orthop Sci 2002; 7: 97-101.
• 121 Haake M, Thon A, Better M. Unchanged c-Fos expression after extracorporeal shock wave therapy: an experimental investigation in rats. Arch Orthop Trauma Surg 2002; 122: 518-521.
• 122 Imboden I, Waldern NM, Wiestner T. et al. Short term analgesic effect of extracorporeal shock wave therapy in horses with proximal palmar metacarpal/plantar metatarsal pain. Vet J 2009; 179: 50-59.
• 123 Waldern NM, Weishaupt MA, Imboden I. et al. Evaluation of skin sensitivity after shock wave treatment in horses. Am J Vet Res 2005; 66: 2095-2100.