I. INTRODUCTION
Shock waves represent a specific kind of mechanical sound pressure waves that are appearing in nature whenever
a sudden release of high amounts of energy occurs. The best-known natural phenomenon is thunder following
lightning. Another example is the bang of an aircraft when breaking the sound barrier.
In medicine shock waves are used at high energy levels for more than 30 years for the disintegration of kidney
stones in lithotripsy (1-2). This fact represents an enormous advantage for low energy shock wave treatment and its
application for tissue regeneration (3). In contrast to other approaches in this field such as (stem) cell treatment or
gene therapies the side-effect profile is well studied for a long time in a huge number of patients. We therefore
know, that no malignancies occur. Moreover, shock waves are in daily clinical use for the treatment of numerous
indications especially in orthopedics and traumatology. These include tendinopathies such as the so-called tennis
elbow or bone non-unions and wound healing disorders. Furthermore, clinical application has been studied for
indications including erectile dysfunction and ischemic heart disease (4-7).
The application in spine injury therefore is deemed a promising approach, especially as these patients are lacking
other feasible and effective treatment options.
II. MAIN SHOCK WAVE EFFECTS
1. Shock waves reduce apoptosis and suppress acute inflammation
In experimental wound healing models, shock waves were described to reduce apoptosis (programmed cell death)
and acute inflammatory reactions (8,9).
In a murine model of severe cutaneous burn wounds the application of shock waves caused decreased infiltration
of the wound bed with inflammatory cells. Treated tissue exhibited lower expression of pro-inflammatory
chemokines compared to untreated control wounds resulting in smaller scar sizes in the treatment group (8).
Similar observations could be made in a skin-flap model in rats: treated flaps showed decreased leucocyte
infiltration leading to enhanced skin flap survival. Interestingly, leucocytes in the peripheral blood of treated animals
exhibited lower expression of hydrogen peroxide (H2O2). Analysis of tissue sections revealed decreased numbers
undergoing programmed cell death after treatment (9).
2. Shock waves modulate inflammation
Inflammation plays a major role in most pathologies. A well-orchestrated inflammatory response to pathological
stimuli is thereby of high importance. A very good example for this fact is the remodeling process after myocardial
infarction: Adequate healing after deterioration of a large amount of cardiomyoctes requires a balanced response between inflammatory and reparative functions. Pro-inflammatory response is needed to replace ischemically harmed
necrotic myocardium with scar tissue. Anti-inflammatory processes are required to create a milieu of regeneration
and enable angiogenesis. Therefore, the common idea to state that inflammation is “bad” is wrong (10) (Fig. 1).
Fig. 1: Biphasic inflammatory response in myocardial infarction. Myocardial
tissue remodelling after infarction (MI) is characterized by an early proinflammatory
phase which leads to phagocytosis of necrotic muscle and debris. In the second
phase reparative monocytes lead to tissue regeneration, angiogenesis and
remodelling of the extracellular matrix (ECM). (10)
In a recent work, we found that shock waves cause a very distinct modulation of the inflammatory response in human endothelial cells via the stimulation of Toll-like receptor 3. Toll- like receptor 3 is part of the innate immune system and is involved in the recognition of double-stranded RNA and fragmented DNA. Its stimulation by shock wave therapy resulted in an early pro-inflammatory initiation phase mediated by IL-6. Subsequently, a middle phase showing suppression of inflammation can be seen before the late anti-inflammatory limitation phase of IL-10 results. This modulation of the inflammatory response is prerequisite for
angiogenesis and repair in injured tissue (11) (Fig. 2). An in-vivo study in Toll-like receptor 3 knock out mice is
currently underway to proof that the stimulation of this innate immune receptor is the pivotal effect of shock wave
treatment and mediates all other effects.
Shock waves represent a specific kind of mechanical sound pressure waves that are appearing in nature whenever
a sudden release of high amounts of energy occurs. The best-known natural phenomenon is thunder following
lightning. Another example is the bang of an aircraft when breaking the sound barrier.
In medicine shock waves are used at high energy levels for more than 30 years for the disintegration of kidney
stones in lithotripsy (1-2). This fact represents an enormous advantage for low energy shock wave treatment and its
application for tissue regeneration (3). In contrast to other approaches in this field such as (stem) cell treatment or
gene therapies the side-effect profile is well studied for a long time in a huge number of patients. We therefore
know, that no malignancies occur. Moreover, shock waves are in daily clinical use for the treatment of numerous
indications especially in orthopedics and traumatology. These include tendinopathies such as the so-called tennis
elbow or bone non-unions and wound healing disorders. Furthermore, clinical application has been studied for
indications including erectile dysfunction and ischemic heart disease (4-7).
The application in spine injury therefore is deemed a promising approach, especially as these patients are lacking
other feasible and effective treatment options.
II. MAIN SHOCK WAVE EFFECTS
1. Shock waves reduce apoptosis and suppress acute inflammation
In experimental wound healing models, shock waves were described to reduce apoptosis (programmed cell death)
and acute inflammatory reactions (8,9).
In a murine model of severe cutaneous burn wounds the application of shock waves caused decreased infiltration
of the wound bed with inflammatory cells. Treated tissue exhibited lower expression of pro-inflammatory
chemokines compared to untreated control wounds resulting in smaller scar sizes in the treatment group (8).
Similar observations could be made in a skin-flap model in rats: treated flaps showed decreased leucocyte
infiltration leading to enhanced skin flap survival. Interestingly, leucocytes in the peripheral blood of treated animals
exhibited lower expression of hydrogen peroxide (H2O2). Analysis of tissue sections revealed decreased numbers
undergoing programmed cell death after treatment (9).
2. Shock waves modulate inflammation
Inflammation plays a major role in most pathologies. A well-orchestrated inflammatory response to pathological
stimuli is thereby of high importance. A very good example for this fact is the remodeling process after myocardial
infarction: Adequate healing after deterioration of a large amount of cardiomyoctes requires a balanced response between inflammatory and reparative functions. Pro-inflammatory response is needed to replace ischemically harmed
necrotic myocardium with scar tissue. Anti-inflammatory processes are required to create a milieu of regeneration
and enable angiogenesis. Therefore, the common idea to state that inflammation is “bad” is wrong (10) (Fig. 1).
Fig. 1: Biphasic inflammatory response in myocardial infarction. Myocardial
tissue remodelling after infarction (MI) is characterized by an early proinflammatory
phase which leads to phagocytosis of necrotic muscle and debris. In the second
phase reparative monocytes lead to tissue regeneration, angiogenesis and
remodelling of the extracellular matrix (ECM). (10)
In a recent work, we found that shock waves cause a very distinct modulation of the inflammatory response in human endothelial cells via the stimulation of Toll-like receptor 3. Toll- like receptor 3 is part of the innate immune system and is involved in the recognition of double-stranded RNA and fragmented DNA. Its stimulation by shock wave therapy resulted in an early pro-inflammatory initiation phase mediated by IL-6. Subsequently, a middle phase showing suppression of inflammation can be seen before the late anti-inflammatory limitation phase of IL-10 results. This modulation of the inflammatory response is prerequisite for
angiogenesis and repair in injured tissue (11) (Fig. 2). An in-vivo study in Toll-like receptor 3 knock out mice is
currently underway to proof that the stimulation of this innate immune receptor is the pivotal effect of shock wave
treatment and mediates all other effects.
3. Shock waves induce angiogenesis
The angiogenic effect of shock wave treatment is probably the most extensively described issue in shock wave science. The
induction of vessel sprouting has been reported in wounds, bone, muscle, heart and skin (12-16) (Fig. 3). Shock waves cause
release of vascular endothelial growth factor (VEGF), which disrupts endothelial cell adhesions and enables migration of
endothelial cells to form capillary structures. The additional up-regulation of placental growth factor (PlGF)
expression in treated tissue leads to maturation of the vessels via pericyte and smooth muscle cell recruitment (15).
Moreover, shock waves cause the release of nitric oxide, another crucial angiogenic player (13). Nitric oxide as
endothelial survival factor has numerous effects on endothelial cells: enhancement of proliferation and migration, inhibition of apoptosis and further vascular endothelial growth factor and fibroblast growth factor (FGF) release (17).
Higher numbers of vessels after shock wave treatment have been shown in small animals, large animals as well as
in clinical studies (15, 18). Patients with ischemic heart disease for instance were described to benefit highly from shock wave treatment resulting in relief of angina symptoms and improvement of heart function (4).
The angiogenic effect of shock wave treatment is probably the most extensively described issue in shock wave science. The
induction of vessel sprouting has been reported in wounds, bone, muscle, heart and skin (12-16) (Fig. 3). Shock waves cause
release of vascular endothelial growth factor (VEGF), which disrupts endothelial cell adhesions and enables migration of
endothelial cells to form capillary structures. The additional up-regulation of placental growth factor (PlGF)
expression in treated tissue leads to maturation of the vessels via pericyte and smooth muscle cell recruitment (15).
Moreover, shock waves cause the release of nitric oxide, another crucial angiogenic player (13). Nitric oxide as
endothelial survival factor has numerous effects on endothelial cells: enhancement of proliferation and migration, inhibition of apoptosis and further vascular endothelial growth factor and fibroblast growth factor (FGF) release (17).
Higher numbers of vessels after shock wave treatment have been shown in small animals, large animals as well as
in clinical studies (15, 18). Patients with ischemic heart disease for instance were described to benefit highly from shock wave treatment resulting in relief of angina symptoms and improvement of heart function (4).
4. Shock waves induce stem cell recruitment
Damaged tissue “cries for help” by expression of chemoattractants responsible for progenitor cell recruitment to the
site of injury. However, this ability is lost in chronically harmed tissue. The very well-respected research group
around Stefanie Dimmeler and Andreas Zeiher in Frankfurt showed that this ability can be regained by the
application of shock waves. In a model of chronic hind limb ischemia in rats they showed that shock wave treatment
24 hours prior to stem cell injection lead to significantly increased recruitment of the injected stem cells to the
injured tissue (19). In a next step, they were able to translate these findings into a clinical setting: Patients with
ischemic heart disease were treated with cardiac shock wave therapy prior to stem cell injection. Again, shock
wave treatment resulted in significant improvement of symptoms and cardiac function compared to patients
receiving only stem cell therapy without prior shock wave treatment (20). These results indicate in a very
impressive manner that shock waves cause enhanced expression of stem cell recruiting chemokines.
However, recent papers show that shock wave treatment not only causes enhanced recruitment of injected stem
cells, but also the mobilization of body-own (endogenous) stem cells. In a chronic hind limb ischemia model in rats
shock wave treatment of the ischemic muscle resulted in higher numbers of circulating stem cells in the peripheral
blood of treated animals (14). Moreover, shock waves caused enhanced recruitment of stem cells to treated
penises in a model of erectile dysfunction in rats (21). Our latest results show that shock wave treatment of
ischemic cardiac muscle causes increased recruitment of stem cells to treated hearts.
Damaged tissue “cries for help” by expression of chemoattractants responsible for progenitor cell recruitment to the
site of injury. However, this ability is lost in chronically harmed tissue. The very well-respected research group
around Stefanie Dimmeler and Andreas Zeiher in Frankfurt showed that this ability can be regained by the
application of shock waves. In a model of chronic hind limb ischemia in rats they showed that shock wave treatment
24 hours prior to stem cell injection lead to significantly increased recruitment of the injected stem cells to the
injured tissue (19). In a next step, they were able to translate these findings into a clinical setting: Patients with
ischemic heart disease were treated with cardiac shock wave therapy prior to stem cell injection. Again, shock
wave treatment resulted in significant improvement of symptoms and cardiac function compared to patients
receiving only stem cell therapy without prior shock wave treatment (20). These results indicate in a very
impressive manner that shock waves cause enhanced expression of stem cell recruiting chemokines.
However, recent papers show that shock wave treatment not only causes enhanced recruitment of injected stem
cells, but also the mobilization of body-own (endogenous) stem cells. In a chronic hind limb ischemia model in rats
shock wave treatment of the ischemic muscle resulted in higher numbers of circulating stem cells in the peripheral
blood of treated animals (14). Moreover, shock waves caused enhanced recruitment of stem cells to treated
penises in a model of erectile dysfunction in rats (21). Our latest results show that shock wave treatment of
ischemic cardiac muscle causes increased recruitment of stem cells to treated hearts.
5. Shock waves improve wound healing
Shock waves promote wound healing in diabetic ulcers and non- healing wounds. This was shown in numerous animal experiments as in cutaneous burn injury models as well as skin flap models. The investigating authors describe reduced wound size and major healing improvement in treated animals. The molecular mechanism of this effect has been mainly linked to the angiogenic and anti-inflammatory properties of shock waves (22).
These results have been translated into the clinic with very encouraging results. Reportedly, chronic soft tissue
profits from shock wave treatment responding with improved healing rates (Fig.5) without any side effects (23).
Interestingly, scar formation seems to be extensively reduced compared to untreated wounds. This effect is mainly
linked to the recruitment of progenitor cells, which might result in functional tissue regeneration rather than
replacement by scar tissue (22). A prospective, randomized phase II trial could show that shock waves accelerate
re-epithelialization of second-degree burn wounds (16).
Shock waves promote wound healing in diabetic ulcers and non- healing wounds. This was shown in numerous animal experiments as in cutaneous burn injury models as well as skin flap models. The investigating authors describe reduced wound size and major healing improvement in treated animals. The molecular mechanism of this effect has been mainly linked to the angiogenic and anti-inflammatory properties of shock waves (22).
These results have been translated into the clinic with very encouraging results. Reportedly, chronic soft tissue
profits from shock wave treatment responding with improved healing rates (Fig.5) without any side effects (23).
Interestingly, scar formation seems to be extensively reduced compared to untreated wounds. This effect is mainly
linked to the recruitment of progenitor cells, which might result in functional tissue regeneration rather than
replacement by scar tissue (22). A prospective, randomized phase II trial could show that shock waves accelerate
re-epithelialization of second-degree burn wounds (16).
6. Shock waves cause pain reduction
Shock waves are described to induce long-term analgesia in chronic musculo-sceletal diseases such as calcifying tendonitis of the shoulder (24), tennis elbow (25) and chronic plantar fasciitis (26). Treated patients report of significant pain relief after treatment. These effects are not very well understood on a molecular level. Experimental studies describe a reduction of the number of neurons immunoreactive for substance P in dorsal root ganglia in rats (27). However, further research needs to be performed in this field.
7. Shock waves induce neuronal regeneration
Shock waves have been described to induce regeneration of peripheral nerves after injury. Authors of the study
dissected the sciatic nerve in rats, rotated it for 180 degrees, and re-attached it via epineural sutures. Shock wave
treated animals showed improved regeneration and ameliorated functional performance of the treated limbs
compared to untreated controls (28).
The strong regenerative potential of shock waves encouraged us to try this technology in a field, where therapeutic
options are very limited: spinal cord injury. In a pilot trial we performed aortic cross clamping in mice for 11 minutes
thereby causing sever ischemic injury to the spinal cord. Animals showed paraplegic symptoms. Shock wave
therapy to the spine was applied immediately while animals were still under anesthesia. Treated animals inhibited
decreased neuronal degeneration, less microglial activation and increased expression of the angiogenic genes
vascular endothelial growth factor and hypoxia inducible factor alpha (Fig.6). However, results are still preliminary
and the experiments still in progress.
Shock waves are described to induce long-term analgesia in chronic musculo-sceletal diseases such as calcifying tendonitis of the shoulder (24), tennis elbow (25) and chronic plantar fasciitis (26). Treated patients report of significant pain relief after treatment. These effects are not very well understood on a molecular level. Experimental studies describe a reduction of the number of neurons immunoreactive for substance P in dorsal root ganglia in rats (27). However, further research needs to be performed in this field.
7. Shock waves induce neuronal regeneration
Shock waves have been described to induce regeneration of peripheral nerves after injury. Authors of the study
dissected the sciatic nerve in rats, rotated it for 180 degrees, and re-attached it via epineural sutures. Shock wave
treated animals showed improved regeneration and ameliorated functional performance of the treated limbs
compared to untreated controls (28).
The strong regenerative potential of shock waves encouraged us to try this technology in a field, where therapeutic
options are very limited: spinal cord injury. In a pilot trial we performed aortic cross clamping in mice for 11 minutes
thereby causing sever ischemic injury to the spinal cord. Animals showed paraplegic symptoms. Shock wave
therapy to the spine was applied immediately while animals were still under anesthesia. Treated animals inhibited
decreased neuronal degeneration, less microglial activation and increased expression of the angiogenic genes
vascular endothelial growth factor and hypoxia inducible factor alpha (Fig.6). However, results are still preliminary
and the experiments still in progress.
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III. REFERENCES
1. Thiel M, Nieswand M, Dörffel M. The use of shock waves in medicine--a tool of
the modern OR: an overview of basic physical principles, history and research. Minim Invasive Ther Allied Technol. 2000;9(3-4):247-53. Review.
2. Chaussy, C., Brendel, W. & Schmiedt, E. Extracorporeally induced destruction of Kidney stones by shock waves. Lancet 2, 1265-1268 (1980).
3. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011 May 19;473(7347):326-35. Review.
4. Chen YJ, Wang CJ, Yang KD, Kuo YR, Huang HC, Huang YT, Sun YC, Wang FS: Extracorporeal shock waves promote healing of collagenase-induced Achilles tendinitis and increase TGF-beta1 and IGF-I expression. J Orthop Res 2004; 22: 854-61
5. Fukumoto Y, Ito A, Uwatoku T, Matoba T, Kishi T, Tanaka H, Takeshita A, Sunagawa K, Shimokawa H: Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006; 17: 63-70
6. Wang CJ, Yang KD, Wang FS, Hsu CC, Chen HH: Shock wave treatment shows dose-dependent enhancement of bone mass and bone strength after fracture of the femur. Bone 2004; 34: 225-30
7. Schaden W, Thiele R, Kolpl C, Pusch M, Nissan A, Attinger CE, Maniscalco-Theberge ME, Peoples GE, Elster EA, Stojadinovic A: Shock wave therapy for acute and chronic soft tissue wounds: a feasibility study. J Surg Res 2007; 143: 1-12
8. Davis TA, Stojadinovic A, Anam K, Amare M, Naik S, Peoples GE, Tadaki D, Elster EA. Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn injury. Int Wound J. 2009 Feb;6(1):11-
9. Kuo YR, Wang CT, Wang FS, Yang KD, Chiang YC, Wang CJ. Extracorporeal shock wave treatment modulates skin fibroblast recruitment and leukocyte infiltration for enhancing extended skin-flap survival. Wound Repair Regen. 2009 Jan-Feb;17(1):80-7.
10. Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010
Jun 8;121(22):2437-45. Review.
11. Holfeld J, Tepeköylü C, Kozaryn R, Urbschat A, Zacharowski K, Grimm M, Paulus P. Shockwave therapy differentially stimulates endothelial
cells: implications on the control of inflammation via toll-Like receptor 3. Inflammation. 2014 Feb;37(1):65-70. doi: 10.1007/s10753-013-9712-1.
12. Kuo YR, Wang CT, Wang FS, Chiang YC, Wang CJ. Extracorporeal shock-wave therapy enhanced wound healing via increasing topical
blood perfusion and tissue regeneration in a rat model of STZ-induced diabetes. Wound Repair Regen. 2009 Jul-Aug;17(4):522-30.
13. Wang CJ, Wang FS, Yang KD, Weng LH, Hsu CC, Huang CS, Yang LC. Shock wave therapy induces neovascularization at the tendon- bone junction. A study in rabbits. J Orthop Res. 2003 Nov;21(6):984-9
14. Tepeköylü C, Wang FS, Kozaryn R, Albrecht-Schgoer K, Theurl M, Schaden W, Ke HJ, Yang Y, Kirchmair R, Grimm M, Wang CJ, Holfeld J. Shock wave treatment induces angiogenesis and mobilizes endogenous CD31/CD34-positive endothelial cells in a hindlimb ischemia model: implications for angiogenesis and vasculogenesis. J Thorac Cardiovasc Surg. 2013 Oct;146(4):971-8.
15. Zimpfer D, Aharinejad S, Holfeld J, Thomas A, Dumfarth J, Rosenhek R, Czerny M, Schaden W, Gmeiner M, Wolner E, Grimm M. Direct epicardial shock wave therapy improves ventricular function and induces angiogenesis in ischemic heart failure. J Thorac Cardiovasc Surg. 2009 Apr;137(4):963-70.
16. Ottomann C, Stojadinovic A, Lavin PT, Gannon FH, Heggeness MH, Thiele R, Schaden W, Hartmann B. Prospective randomized phase II Trial of accelerated reepithelialization of superficial second-degree burn wounds using extracorporeal shock wave therapy. Ann Surg. 2012 Jan;255(1):23-9.
17. Cooke JP, Losordo DW. Nitric oxide and angiogenesis. Circulation. 2002 May 7;105(18):2133-5.
18. Nishida T, Shimokawa H, Oi K, Tatewaki H, Uwatoku T, Abe K, Matsumoto Y, Kajihara N, Eto M, Matsuda T, Yasui H, Takeshita A, Sunagawa K. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation. 2004 Nov 9;110(19):3055-61.
19. Aicher A, Heeschen C, Sasaki K, Urbich C, Zeiher AM, Dimmeler S. Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation. 2006 Dec 19;114(25):2823-30.
20. Assmus B, Walter DH, Seeger FH, Leistner DM, Steiner J, Ziegler I, Lutz A, Khaled W, Klotsche J, Tonn T, Dimmeler S, Zeiher AM. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA.
2013 Apr 17;309(15):1622-31.
21. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, Lin CS. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med. 2013 Mar;10(3):738-46. doi: 10.1111/jsm.12024. Epub 2012 Dec 17.
22. Mittermayr R, Antonic V, Hartinger J, Kaufmann H, Redl H, Téot L, Stojadinovic A, Schaden W. Extracorporeal shock wave therapy (ESWT) for wound healing: technology, mechanisms, and clinical efficacy. Wound Repair Regen. 2012 Jul-Aug;20(4):456-65.
23. Schaden W, Thiele R, Kölpl C, Pusch M, Nissan A, Attinger CE, Maniscalco-Theberge ME, Peoples GE, Elster EA, Stojadinovic A. Shock wave therapy for acute and chronic soft tissue wounds: a feasibility study. J Surg Res. 2007
24. Loew M, Daecke W, Kusnierczak D, Rahmanzadeh M, Ewerbeck V. Shock-wave therapy is effective for chronic calcifying tendinitis of the shoulder. J Bone Joint Surg Br. 1999 Sep;81(5):863-7.
25. Rompe JD, Hopf C, Küllmer K, Heine J, Bürger R, Nafe B. Low-energy extracorporal shock wave therapy for persistent tennis elbow. Int Orthop. 1996;20(1):23-7.
26. Vahdatpour B, Sajadieh S, Bateni V, Karami M, Sajjadieh H. Extracorporeal shock wave therapy in patients with plantar fasciitis. A randomized, placebo-controlled trial with ultrasonographic and subjective outcome assessments. J Res Med Sci. 2012 Sep;17(9):834-8.
27. Vahdatpour B, Sajadieh S, Bateni V, Karami M, Sajjadieh H. Extracorporeal shock wave therapy in patients with plantar fasciitis. A randomized, placebo-controlled trial with ultrasonographic and subjective outcome assessments. J Res Med Sci. 2012 Sep;17(9):834-8.
28. Hausner T, Pajer K, Halat G, Hopf R, Schmidhammer R, Redl H, Nógrádi A. Improved rate of peripheral nerve regeneration induced by extracorporeal shock wave treatment in the rat. Exp Neurol. 2012 Aug;236(2):363-70.
1. Thiel M, Nieswand M, Dörffel M. The use of shock waves in medicine--a tool of
the modern OR: an overview of basic physical principles, history and research. Minim Invasive Ther Allied Technol. 2000;9(3-4):247-53. Review.
2. Chaussy, C., Brendel, W. & Schmiedt, E. Extracorporeally induced destruction of Kidney stones by shock waves. Lancet 2, 1265-1268 (1980).
3. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011 May 19;473(7347):326-35. Review.
4. Chen YJ, Wang CJ, Yang KD, Kuo YR, Huang HC, Huang YT, Sun YC, Wang FS: Extracorporeal shock waves promote healing of collagenase-induced Achilles tendinitis and increase TGF-beta1 and IGF-I expression. J Orthop Res 2004; 22: 854-61
5. Fukumoto Y, Ito A, Uwatoku T, Matoba T, Kishi T, Tanaka H, Takeshita A, Sunagawa K, Shimokawa H: Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006; 17: 63-70
6. Wang CJ, Yang KD, Wang FS, Hsu CC, Chen HH: Shock wave treatment shows dose-dependent enhancement of bone mass and bone strength after fracture of the femur. Bone 2004; 34: 225-30
7. Schaden W, Thiele R, Kolpl C, Pusch M, Nissan A, Attinger CE, Maniscalco-Theberge ME, Peoples GE, Elster EA, Stojadinovic A: Shock wave therapy for acute and chronic soft tissue wounds: a feasibility study. J Surg Res 2007; 143: 1-12
8. Davis TA, Stojadinovic A, Anam K, Amare M, Naik S, Peoples GE, Tadaki D, Elster EA. Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn injury. Int Wound J. 2009 Feb;6(1):11-
9. Kuo YR, Wang CT, Wang FS, Yang KD, Chiang YC, Wang CJ. Extracorporeal shock wave treatment modulates skin fibroblast recruitment and leukocyte infiltration for enhancing extended skin-flap survival. Wound Repair Regen. 2009 Jan-Feb;17(1):80-7.
10. Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010
Jun 8;121(22):2437-45. Review.
11. Holfeld J, Tepeköylü C, Kozaryn R, Urbschat A, Zacharowski K, Grimm M, Paulus P. Shockwave therapy differentially stimulates endothelial
cells: implications on the control of inflammation via toll-Like receptor 3. Inflammation. 2014 Feb;37(1):65-70. doi: 10.1007/s10753-013-9712-1.
12. Kuo YR, Wang CT, Wang FS, Chiang YC, Wang CJ. Extracorporeal shock-wave therapy enhanced wound healing via increasing topical
blood perfusion and tissue regeneration in a rat model of STZ-induced diabetes. Wound Repair Regen. 2009 Jul-Aug;17(4):522-30.
13. Wang CJ, Wang FS, Yang KD, Weng LH, Hsu CC, Huang CS, Yang LC. Shock wave therapy induces neovascularization at the tendon- bone junction. A study in rabbits. J Orthop Res. 2003 Nov;21(6):984-9
14. Tepeköylü C, Wang FS, Kozaryn R, Albrecht-Schgoer K, Theurl M, Schaden W, Ke HJ, Yang Y, Kirchmair R, Grimm M, Wang CJ, Holfeld J. Shock wave treatment induces angiogenesis and mobilizes endogenous CD31/CD34-positive endothelial cells in a hindlimb ischemia model: implications for angiogenesis and vasculogenesis. J Thorac Cardiovasc Surg. 2013 Oct;146(4):971-8.
15. Zimpfer D, Aharinejad S, Holfeld J, Thomas A, Dumfarth J, Rosenhek R, Czerny M, Schaden W, Gmeiner M, Wolner E, Grimm M. Direct epicardial shock wave therapy improves ventricular function and induces angiogenesis in ischemic heart failure. J Thorac Cardiovasc Surg. 2009 Apr;137(4):963-70.
16. Ottomann C, Stojadinovic A, Lavin PT, Gannon FH, Heggeness MH, Thiele R, Schaden W, Hartmann B. Prospective randomized phase II Trial of accelerated reepithelialization of superficial second-degree burn wounds using extracorporeal shock wave therapy. Ann Surg. 2012 Jan;255(1):23-9.
17. Cooke JP, Losordo DW. Nitric oxide and angiogenesis. Circulation. 2002 May 7;105(18):2133-5.
18. Nishida T, Shimokawa H, Oi K, Tatewaki H, Uwatoku T, Abe K, Matsumoto Y, Kajihara N, Eto M, Matsuda T, Yasui H, Takeshita A, Sunagawa K. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation. 2004 Nov 9;110(19):3055-61.
19. Aicher A, Heeschen C, Sasaki K, Urbich C, Zeiher AM, Dimmeler S. Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation. 2006 Dec 19;114(25):2823-30.
20. Assmus B, Walter DH, Seeger FH, Leistner DM, Steiner J, Ziegler I, Lutz A, Khaled W, Klotsche J, Tonn T, Dimmeler S, Zeiher AM. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA.
2013 Apr 17;309(15):1622-31.
21. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, Lin CS. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med. 2013 Mar;10(3):738-46. doi: 10.1111/jsm.12024. Epub 2012 Dec 17.
22. Mittermayr R, Antonic V, Hartinger J, Kaufmann H, Redl H, Téot L, Stojadinovic A, Schaden W. Extracorporeal shock wave therapy (ESWT) for wound healing: technology, mechanisms, and clinical efficacy. Wound Repair Regen. 2012 Jul-Aug;20(4):456-65.
23. Schaden W, Thiele R, Kölpl C, Pusch M, Nissan A, Attinger CE, Maniscalco-Theberge ME, Peoples GE, Elster EA, Stojadinovic A. Shock wave therapy for acute and chronic soft tissue wounds: a feasibility study. J Surg Res. 2007
24. Loew M, Daecke W, Kusnierczak D, Rahmanzadeh M, Ewerbeck V. Shock-wave therapy is effective for chronic calcifying tendinitis of the shoulder. J Bone Joint Surg Br. 1999 Sep;81(5):863-7.
25. Rompe JD, Hopf C, Küllmer K, Heine J, Bürger R, Nafe B. Low-energy extracorporal shock wave therapy for persistent tennis elbow. Int Orthop. 1996;20(1):23-7.
26. Vahdatpour B, Sajadieh S, Bateni V, Karami M, Sajjadieh H. Extracorporeal shock wave therapy in patients with plantar fasciitis. A randomized, placebo-controlled trial with ultrasonographic and subjective outcome assessments. J Res Med Sci. 2012 Sep;17(9):834-8.
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