Content uploaded by Antal Nogradi
Author content
All content in this area was uploaded by Antal Nogradi on Jan 05, 2021
Content may be subject to copyright.
Provided for non-commercial research and educational use only.
Not for reproduction, distribution or commercial use.
This chapter was originally published in the book International Review of
Neurobiology, Vol. 109 published by Elsevier, and the attached copy is provided by
Elsevier for the author's benefit and for the benefit of the author's institution, for non-
commercial research and educational use including without limitation use in
instruction at your institution, sending it to specific colleagues who know you, and
providing a copy to your institution’s administrator.
All other uses, reproduction and distribution, including without limitation commercial
reprints, selling or licensing copies or access, or posting on open internet sites, your
personal or institution’s website or repository, are prohibited. For exceptions,
permission may be sought for such use through Elsevier's permissions site at:
http://www.elsevier.com/locate/permissionusematerial
From Thomas Hausner, Antal Nógrádi, The Use of Shock Waves in Peripheral Nerve
Regeneration:New Perspectives?. In Stefano Geuna, Isabelle Perroteau, Pierluigi Tos
and Bruno Battiston, editors: International Review of Neurobiology, Vol. 109,
Burlington: Academic Press, 2013, pp. 85-98.
ISBN: 978-0-12-420045-6
© Copyright 2013 Elsevier Inc.
Academic Press
CHAPTER THREE
The Use of Shock Waves in
Peripheral Nerve Regeneration:
New Perspectives?
Thomas Hausner*
,†,{
, Antal Nógrádi*
,},1
*Austrian Cluster for Tissue Regeneration and Ludwig Boltzmann Institute for Experimental and Clinical
Traumatology at the Research Centre for Trauma of the Austrian Workers’ Compensation Board (AUVA),
Vienna, Austria
†
Department for Trauma Surgery and Sports Traumatology, Paracelsus Medical University, Salzburg, Austria
{
Department for Surgery, State Hospital Hainburg, Hainburg, Austria
}
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Szeged,
Hungary
1
Corresponding author: e-mail address: nogradi.antal@med.u-szeged.hu
Contents
1. Introduction 86
2. Features of Peripheral Nerve Regeneration in Rodents and Humans: How to
Speed Up Slow Regeneration? 87
3. Presumed Biological Effects of ESWT 88
4. Effects of ESWT on Peripheral Nerves 89
4.1 Effects of ESWT on sensory nerves 89
4.2 Effects of ESWT on motor nerves 91
5. Conclusion 93
Acknowledgments 96
References 96
Abstract
Low-energy extracorporeal shock wave treatment (ESWT) is a relatively new therapeutic
tool that is widely used for the treatment of epicondylitis and plantar fasciitis and to
foster bone and wound healing. Shock waves, sonic pulses with high energy impact,
are thought to induce biochemical changes within the targeted tissues through
mechanotransduction. The biological effects of ESWT are manifested in improved vas-
cularization, the local release of growth factors, and local anti-inflammatory effects, but
the target cells too are influenced.
ESWT appears to have differential effects on peripheral nerves and has been proved
to promote axonal regeneration after axotomy. This review discusses the effects of ESWT
on intact and injured peripheral nerves and suggests a multiple mechanism of action.
International Review of Neurobiology, Volume 109 #2013 Elsevier Inc.
ISSN 0074-7742 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-420045-6.00003-1
85
Author's personal copy
1. INTRODUCTION
Shock waves are transient short-term sonic pulses with a high-peak
pressure up to 100 Mpa, followed by a negative pressure of about
5–10 MPa. They have rapid rise times of the order of nanoseconds and short
pulse durations ranging up to 5 ms. Shock waves are induced electro-
hydraulically and then reflected by a focusing device with either parabolic
or ellipsoid geometry. The spatial shape of the pressure field depends on
the form of this reflector, and shock waves may therefore be applied in a
focused or a defocused manner. Moreover, shock waves can be applied
extra- or intracorporeally and either low- or high energy levels may be used.
Focused shock waves are used to disintegrate solid aggregations such as
kidney stones or solid deposits in tissues (calcified tendons) that usually con-
tain minerals. For these applications, a high energy level is necessary in order
to destroy the kidney stones or calcifications. The high energy transmission
in cases of focused shock wave treatment necessitates intravenous sedation or
even general anesthesia as this procedure is often very painful. Defocused
shock waves are administered in soft tissue diseases such as chronic wounds
or ulcerations, and recent applications include ischemic heart disease too
(Zimpfer et al., 2009). Defocused shock waves display a different shape of
acoustic pressure distribution and hence a larger tissue area is affected.
Accordingly, defocused low-energy shock wave treatment does not induce
pain in most cases.
Although most shock wave treatments are applied extracorporeally
(extracorporeal shock wave treatment, ESWT), this treatment does not pro-
duce satisfactory results in all cases. In this situation, the use of intracorporeal
shock waves may be suggested, for example, endoscopic intracorporeal
shock wave lithotripsy for the treatment of bile stones refractive to tradi-
tional endoscopic methods (Attila, May, & Kortan, 2008).
Shock wave treatment may also be divided into high- and low-transfer-
energy categories. While both treatment modalities are of therapeutic value,
high-energy shock wave treatments are typically used for the destruction of
solid aggregations inside or outside tissues, whereas low-energy treatment is
administered for tissue repair and regeneration (Mittermayer et al., 2012).
The use of shock waves as a therapeutic approach has a relatively short
history. Shock wave treatment was first used for the destruction of urinary
stones, including those in the kidney, in the 1980s (Chaussy et al., 1982).
A decade later, two groups reported successful treatment of calcifying
86 Thomas Hausner and Antal Nógrádi
Author's personal copy
tendinopathies of the shoulder by the disintegration of calcified deposits, and
shortly afterward shock wave treatment was introduced into other fields of
medicine. ESWT has become a widely utilized therapeutic tool in regener-
ative medicine in recent years. It is frequently and successfully administered
in painful conditions such as humero-radial epicondylitis (tennis elbow),
plantar fasciitis, and other pathological conditions affecting bone-related
structures. Chronic wounds, ulcerations, and ischemic heart failure have also
been successfully targeted by ESWT (Mittermayer et al., 2012; Nishida
et al., 2004; Zimpfer et al., 2009).
In this review, we focus on the use and effects of defocused low-energy
ESWT in the peripheral nervous system.
2. FEATURES OF PERIPHERAL NERVE REGENERATION
IN RODENTS AND HUMANS: HOW TO
SPEED UP SLOW REGENERATION?
Injuries to peripheral nerves are followed by a rapid process of degen-
erative events called Wallerian degeneration. These events include changes
that are effective in the anterograde direction from the injury site, that is, the
disconnection of axons from the target organ, for example, the motor end-
plate, the breakdown of axon and myelin in the distal stump of the injured
nerve, and changes that affect the proximal nerve stump (degeneration up to
the first Ranvier node) and mainly the cell body retrograde from the injury:
chromatolysis (the classical term for the disintegration of the rough
endoplasmatic reticulum), dislocation of the nucleus, and shrinkage of the
dendritic tree. The degenerative processes are followed by regenerative
events, provided that the injured nerve stumps are in close vicinity and
the regenerating axons from the proximal stump are able to enter the vacated
endoneural sheaths in the distal stump. The regrowth of axons is supported
by the rapid proliferation of Schwann cells in the distal stump providing a
contact guide for them. The proliferating Schwann cells align to form the
bands of Bu
¨ngner and restructure the extracellular matrix that contains
growth-promoting molecules such as laminin and fibronectin. The growth
cone of the regenerating axons actively synthesizes transmembrane integrin
molecules, for example, integrin-type alpha5-beta1, which interacts with
fibronectin, thereby ensuring the axonal growth. In this way, all the condi-
tions required for the successful regeneration and reinnervation of the targets
are provided.
87The Use of Shock Waves in Peripheral Nerve Regeneration: New Perspectives?
Author's personal copy
While axons in the rodent peripheral nervous system regenerate at a
speed of 2–3 mm/day, so that relatively short distances are rapidly bridged
by growing axons, human peripheral nerve injuries are followed by a
slower rate of regeneration (1 mm/day). Given the fact that some motor
and sensory axons projecting into the lower limb may reach or exceed a
length of 1 m, the regeneration and reinnervation of peripheral targets
may clearly be an extremely slow process. The slow regeneration in human
peripheral nerves is further hampered by the predegenerative process occur-
ring in the distal parts of the nerve to be occupied by regenerating fibers
(Gordon, 2010; Gordon et al., 2009).
In view of the long recovery and rehabilitation process after injuries to
peripheral nerves, there is a great need for the development of procedures
that promote peripheral nerve regeneration in humans and thereby decrease
the related social and health-care costs. While the effects of shock waves on
wound healing, (Schaden et al., 2007), bone regeneration (Ogden, Alvarez,
Levitt, Cross, & Marlow, 2001), and the integration of skin grafts (Kuo et al.,
2009; Stojadinovic et al., 2008) have been extensively studied, very little is
known as concerns its effects on peripheral nerve regeneration (Hausner
et al., 2012; Wu, Lun, Chen, & Chong, 2007).
3. PRESUMED BIOLOGICAL EFFECTS OF ESWT
Shock waves are mechanical events that can stimulate tissues and espe-
cially cells. The conversion of physical forces into biochemical signals is a
fundamental process required for the development and the physiology of
organisms. This process is referred to as mechanotransduction. Physical
forces exert a direct influence on protein folding, and force-induced effects
on the three-dimensional structures of proteins are therefore involved in a
general mechanism through which the activities of enzymes or the interac-
tions between proteins may lead to signal modification (Orr, Helmke,
Blackmann, & Schwartz, 2006). The manner in which ESWT-induced
mechanotransduction is manifested in target cells and tissues is still not clear.
There are a number of proved facts or theories concerning the cascade of
actions stemming from shock wave treatment and resulting in angiogenesis
or neovascularization (Sadoun and Reed, 2003; Stojadinovic et al., 2008;
Wang et al., 2004), anti-inflammatory effects (Davis et al., 2009), the release
of growth factors (Hausdorf et al., 2011), and the activation of progenitor
cells and stem cells (Mittermayer et al., 2012; Sadoun and Reed, 2003).
88 Thomas Hausner and Antal Nógrádi
Author's personal copy
There are various mechanisms behind the effects in tissues treated with
shock waves. It has been reported that angiogenesis is induced by increased
levels of vascular endothelial growth factor-A, which in turn is triggered by
upregulated activities of nitric oxide synthase (NOS), and extracellular
signal-regulated kinase. On the other hand, enhanced NOS activity also
appears to be responsible for the activation of hypoxia-inducible factor-1
in a variety of cells, depending on the target of ESWT. Low-energy shock
wave treatment has likewise proved to be effective in downregulating
immune responses in acute wounds. ESWT has been reported to reduce
the invasion of macrophages and polymorphonuclear leucocytes into the
wound area, together with the suppressed production of proinflammatory
cytokines and chemokines at the wound matrix (Davis et al., 2009; Kuo
et al., 2009). Similar to its role in inducing angiogenesis in shock wave-
treated tissues, the regulatory function of NOS has been suggested in the
downregulation of inflammatory events in these conditions (Fig. 3.1;
Mariotto et al., 2009). Others have described the increased release of fibro-
blast growth factor-2, acting on osteoblasts (Hausdorf et al., 2011), while
osteocalcin, a major bone protein playing an important role in bone miner-
alization, is reportedly upregulated in regenerating the bone after ESWT
(Martini et al., 2003). In contrast with these molecules, the role of trans-
forming growth factor-beta remains controversial (Hausdorf et al., 2011;
Martini et al., 2003).
It has been suggested that mesenchymal stem cells may differentiate
toward tissue-specific progenitor cells such as osteoblasts in response to
ESWT (Chen et al., 2004), and the moderate recruitment of endothelial
progenitor cells has been described (Tinazzi et al., 2011). However, the
extent to which these mechanisms are able to contribute to the tissue repair
following ESWT is not clear at present.
4. EFFECTS OF ESWT ON PERIPHERAL NERVES
4.1. Effects of ESWT on sensory nerves
Shock waves have been used extensively to study their effects on sensory
nerves and nerve endings. Application of 1000 impulses of shock waves
(0.08 mJ/mm, 2.4 Hz) resulted in the degeneration of sensory nerve fibers
and endings followed by reinnervation of the affected skin areas (Ohtori
et al., 2001). These changes were accompanied by the reversible and rapid
loss of the immunohistochemical markers protein gene product 9.5 and
89The Use of Shock Waves in Peripheral Nerve Regeneration: New Perspectives?
Author's personal copy
calcitonin gene-related peptide. However, a second application of the same
dose of shock waves had a cumulative effect on the treated nerves, leading to
delayed reinnervation (Takahashi, Ohtori, Saisu, Moriya, & Wada, 2006). It
appears, therefore, that shock wave-treated nerves develop a “memory
effect” after the first treatment, and ESWT repeated shortly after the first
treatment is not beneficial. It is expected that ESWT induces subtle changes
in the affected neurones whose axons have been treated. Murata et al. (2006)
detected an increased expression of activating transcription factor 3 (ATF-3)
and growth-associated phosphoprotein 43 (GAP-43) in dorsal root ganglion
neurones of shock wave-treated rats, indicating that the molecular changes
after ESWT are not restricted to the treated axons: their cell bodies are also
Figure 3.1 Schematic drawing depicting the sites of action by shock waves in various
tissues (with the exception of peripheral nerves). The target cells of shock wave treat-
ment are embedded in the extracellular matrix, surrounded by various other cell types,
including resident and invading mononuclear and polymorphonuclear immune cells.
ESWT has been proved to induce the release of growth factors (e.g., FGF-2) from the
cells surrounding the target cells, to improve angiogenesis within the tissues, and to
reduce the secretion of inflammatory cytokines and the invasion of immune cells. On
the other hand, tissue-specific target cells are known to secrete factors such as
hypoxia-inducible factor-1 (HIF-1). Several of these processes are regulated via the acti-
vation of nitric oxide synthase (NOS); it should be noted that the extent to which these
processes are induced varies with the type of tissue (ECM, extracellular matrix; ERK,
extracellular signal-regulated kinase; FGF-2, fibroblast growth factor-2; VEGF-A, vascular
endothelial growth factor-A; SW, shock waves).
90 Thomas Hausner and Antal Nógrádi
Author's personal copy
activated in a retrograde manner. The question remains open as to whether
doses of ESWT in the therapeutic range would induce similar changes as the
2000 impulses applied in this study. ATF-3 and GAP-43 are markers
thought to be associated with the activation of neurones and glial cells
(Schwann cells) after peripheral nerve injuries (Hunt et al., 2004; Saito
and Dahlin, 2008).
As regards the dose–effect relationship of ESWT on peripheral nerves, a
large body of evidence suggests that shock wave doses greater than 900
impulses combined with a flux density of 0.08 mJ/mm
2
induce damage
to the affected nerves, manifested in impaired electrophysiological conduc-
tion parameters (Wu et al., 2007), a disrupted neurofilament staining pattern
of the treated axons (Hausner et al., 2012), and degeneration of the myelin
sheaths at the levels of light and electron microscopy (Bolt et al., 2004).
These doses appeared to damage motor and sensory nerves equally (Bolt
et al., 2004; Wu et al., 2007). Our experimental and clinical experience indi-
cates that the therapeutically applicable dose for the promotion of nerve
regeneration without side effects is likely to be lower than 500 impulses
(0.1 mJ/mm
2
, 4 Hz) (Hausner et al., 2012). The effect of such doses is highly
dependent on the depth of the target tissue and the treated surface area.
4.2. Effects of ESWT on motor nerves
The question arose of whether doses of shock wave treatment that did not
cause degenerative events in the affected peripheral nerve segments would
foster the regeneration of injured axons in a rodent model. It was clearly
demonstrated that ESWT applied at a dose of 300 impulses and 0.1 mJ/
mm
2
did not induce the disintegration of neurofilaments within the axons
of the sciatic nerve (Hausner et al., 2012). The efficacy of this ESWT scheme
was tested in an autologous rat sciatic nerve model, where an 8-mm long
autograft was excised and coapted with the proximal and distal stumps.
When shock wave treatment was applied immediately after surgical recon-
struction, a significantly improved rate of axonal regeneration was observed
as early as 3 weeks after the injury. Not only were more regenerating axons
found in the reinnervated distal stump of the shock wave-treated nerves, but
also this early reinnervation was accompanied by moderate values of axon
conduction beyond the distal coaptation site. The morphological and func-
tional reinnervation of the denervated hind limb muscles could be expected
only at later time points. Functional tests revealed a clear improvement in the
ESWT animals from 4 weeks onward, but this difference in improved
91The Use of Shock Waves in Peripheral Nerve Regeneration: New Perspectives?
Author's personal copy
locomotor pattern was no longer detectable from week 10 after surgery.
Twelve weeks after injury, none of the morphological, functional, or elec-
trophysiological parameters indicated differences between the treated and
the untreated animals, with the exception of the conduction velocity, which
was still significantly higher in the ESWT group (Fig. 3.2).
Figure 3.2 Axonal regeneration in control and extracorporeal shock wave-treated
(ESWT) peripheral nerves 3 weeks and 3 months after surgery. (A) The columns show
the numbers of myelinated fibers found in the middle of the graft and 2 mm proximal
and distal to the graft in ESWT and control animals 3 weeks after axotomy (left). The
92 Thomas Hausner and Antal Nógrádi
Author's personal copy
Ultrastructural analysis of the nerve grafts 3 weeks after the injury rev-
ealed that not only were there more regenerated and well-myelinated axons
in the ESWT nerves, but also the endoneurium was free from reactive cells
and degenerated myelin profiles, which were present in abundance in the
untreated nerves (Fig. 3.3;Hausner et al., 2012). These findings indicated
that the improved rate of axonal regeneration and the clearing-up of the
degenerated structures in the denervated nerves are strongly related. It
remains for future studies to establish whether either of these processes
enjoys priority over the other in the temporal sequence of events.
5. CONCLUSION
Shock waves were introduced into the arsenal of modern human med-
ical therapy some 30 years ago (Shrivastava and Kailash, 2005; Thiel, 2001).
Following the initial treatment trials on urolithiasis, extracorporeal shock
waves were introduced both preclinically and clinically for the treatment
of acute and chronic soft and hard tissue healing problems (Ogden et al.,
2001). In most cases, improvements in the soft and hard tissue healing pro-
cesses were found to be associated with increased levels of vascularization,
and this mechanism of action was therefore considered to be a general,
but not overall scenario for shock wave-induced improvement (Wang
et al., 2004; Yan, Zeng, Chai, Luo, & Li, 2008; Zimpfer et al., 2009). How-
ever, it has subsequently been demonstrated that other nonvascular mech-
anisms contribute to the tissue repair (for details, see Fig. 3.1).
numbers of myelinated axons in the graft and distal to the grafting site are much higher
in the ESWT animals than in the controls. There was no significant difference between
the controls and the ESWT animals in the numbers of myelinated axons distal to the
graft 3 months after axotomy and grafting (right). *Significant difference (p<0.05)
between the control and the ESWT groups by ANOVA, computed by using Tukey’s
all pairwise multiple comparison procedures. (B–F) Photographs of semithin cross-
sections from the proximal stump (B), the middle of the graft (C, D), and the distal stump
(E, F) 3 weeks after axotomy. The shock wave-treated peripheral nerves (ESWT) contain
more myelinated axons, while the control nerves display far fewer regenerated axons
(arrows) and are full of degenerated myelin sheaths and reactive cells. (G, H): Photo-
graphs of semithin cross-sections from the distal stump 3 months after axotomy. There
is no striking difference between the ESWT and control nerves, although the myelin
sheaths of the regenerated axons appear thinner than those seen in the intact proximal
stump (B). Methylene blue–thionin staining according to Rüdeberg, scale bar ¼25 mm.
This figure is reproduced from the publication by Hausner et al. (2012), with the kind per-
mission of Elsevier/Rightslink.
93The Use of Shock Waves in Peripheral Nerve Regeneration: New Perspectives?
Author's personal copy
Figure 3.3 Electron microscopic photographs of control (A) and shock wave-treated
peripheral nerves 3 weeks after surgery. Panel (A) shows several degenerated myelin
sheaths (D) engulfed by macrophages (M). A few myelinated regenerated axons
(arrows) too can be seen. In panel (B), a high number of myelinated axons are present
Author's personal copy
without reactive cells, but surrounded by Schwann cells. Panel (C) presents a higher
magnification of the framed area in (B). Note the remyelinating Schwann cells (Sch)
and some collagen bundles (C) in the endoneurium. Scale bar in (A) and (B) ¼2mm,
in (C)¼1mm. This figure is reproduced from the publication by Hausner et al. (2012), with
the kind permission of Elsevier/Rightslink.
Figure 3.4 Schematic drawing displaying the possible sites of action of ESWT in a reg-
enerating peripheral nerve and related cell bodies. In an untreated peripheral nerve,
regenerating neurites enter the vacated endoneural sheaths of the degenerated distal
peripheral nerve stump and grow along the aligned proliferating Schwann cells (bands
of Büngner), provided that the proximal and distal stumps are sufficiently close to each
other. It is suggested here that ESWT may improve the rate of axonal regeneration
through the activation of integrin molecules expressed on the axonal growth cones,
thereby promoting stronger binding to the various extracellular molecules, such as lam-
inin and fibronectin. The rate of proliferation of Schwann cells in the distal stump may
also increase, in conjunction with a more pronounced macrophage activity, which
results in the faster and more effective clearance of myelin debris. These actions may
have a cumulative effect on nerve regeneration, leading to a faster and more accurate
reinnervation process. The changes in the distal stump of the nerve and the more effec-
tive axonal regeneration is accompanied by molecular changes in the related cell
bodies, that is, upregulation of transcription factor ATF-3 and GAP-43. Apart from these
actions marked in red, it appears conceivable that many other molecular mechanisms
too are upregulated in order to support extensive axonal growth. The term endoneural
sheath refers to the fine network of reticular fibers and extracellular matrix molecules
around each myelinated axon as part of the endoneurium (ATF-3, activating transcrip-
tion factor-3; ECM, extracellular matrix; GAP-43, growth-associated phosphoprotein-43;
SW, shock waves).
Author's personal copy
The present review has surveyed the findings that describe the effects of
shock waves on intact and injured peripheral nerves. Although only limited
information is available on the mechanism of action of shock wave treatment
on peripheral nerves, improved vascularization does not appear to play a
direct role in promoting axon regeneration after axotomy. Axonal regener-
ation in the peripheral nerves is known to be promoted by several cellular
and molecular components of the nerve, including the coupling of integrin
molecules situated on the axonal growth cone membrane with the abundant
extracellular molecules (Lefcort, Venstrom, McDonald, & Reichardt, 1992;
Low, No
´gra
´di, Vrbova
´,& Greensmith, 2003; Tomaselli et al., 1993), the
proliferation of activated Schwann cells in the degenerated distal stump of
the nerve (Stoll and Mu
¨ller, 1999), and the clear role played by activated
macrophages (Dailey, Avellino, Benthem, Silver, & Kliot, 1998; Horie
et al., 2004; Hughes and Perry, 2000) in the removal of myelin debris
(Fig. 3.4). We therefore suggest that ESWT may augment and potentiate
the mechanisms described earlier in a regenerating peripheral nerve seg-
ment. It is to be expected that ESWT will become more widely used in
the treatment of injuries and pathological conditions affecting peripheral
nerves.
ACKNOWLEDGMENTS
The authors are indebted to the Lorenz Bo
¨hler Fonds for financial support. The excellent
artwork of Mr. Ga
´bor Ma
´rton is gratefully acknowledged. We thank Dr. David Durham
for a critical reading of the chapter.
REFERENCES
Attila, T., May, G. R., & Kortan, P. (2008). Nonsurgical management of an impacted
mechanical lithotriptor with fractured traction wires: Endoscopic intracorporeal electro-
hydraulic shock wave lithotripsy followed by extra-endoscopic mechanical lithotripsy.
Canadian Journal of Gastroenterology,22(8), 699–702.
Bolt, D. M., Burba, D. J., Hubert, J. D., Strain, G. M., Hosgood, G. L., Henk, W. G., et al.
(2004). Determination of functional and morphologic changes in palmar digital nerves
after nonfocused extracorporeal shock wave treatment in horses. American Journal of Vet-
erinary Research,65(12), 1714–1718.
Chaussy, C., Schmiedt, E., Jocham, D., Brendel, W., Forssmann, B., & Walter, V. (1982).
First clinical experience with extracorporeally induced destruction of kidney stones by
shock waves. The Journal of Urology,127, 417.
Chen, Y. J., Wurtz, T., Wang, C. J., Kuo, Y. R., Yang, K. D., Huang, H. C., et al. (2004).
Recruitment of mesenchymal stem cells and expression of TGF-beta 1 and VEGF in the
early stage of shock wave-promoted bone regeneration of segmental defect in rats. Journal
of Orthopaedic Research,22(3), 526–534.
Dailey, A. T., Avellino, A. M., Benthem, L., Silver, J., & Kliot, M. (1998). Complement
depletion reduces macrophage infiltration and activation during Wallerian degeneration
and axonal regeneration. The Journal of Neuroscience,18(17), 6713–6722.
96 Thomas Hausner and Antal Nógrádi
Author's personal copy
Davis, T. A., Stojadinovic, A., Anam, K., Amare, M., Naik, S., Peoples, G. E., et al. (2009).
Extracorporeal shock wave therapy suppresses the early proinflammatory immune
response to a severe cutaneous burn injury. International Wound Journal,6, 11–21.
Gordon, T. (2010). The physiology of neural injury and regeneration: The role of neuro-
trophic factors. Journal of Communication Disorders,43(4), 265–273.
Gordon, T., Chan, K. M., Sulaiman, O. A., Udina, E., Amirjani, N., & Brushart, T. M.
(2009). Accelerating axon growth to overcome limitations in functional recovery after
peripheral nerve injury. Neurosurgery,65(4), A132–A144.
Hausdorf, J., Sievers, B., Schmitt-Sody, M., Jansson, V., Maier, M., & Mayer-Wagner, S.
(2011). Stimulation of bone growth factor synthesis in human osteoblasts and fibroblasts
after extracorporeal shock wave application. Archives of Orthopaedic and Trauma Surgery,
131(3), 303–309.
Hausner, T., Pajer, K., Halat, G., Hopf, R., Schmidhammer, R., Redl, H., et al. (2012).
Improved rate of peripheral nerve regeneration induced by extracorporeal shock wave
treatment in the rat. Experimental Neurology,236(2), 363–370. http://dx.doi.org/
10.1016/j.expneurol.2012.04.019, Epub May 1, 2012.
Horie, H., Kadoya, T., Hikawa, N., Sango, K., Inoue, H., Takeshita, K., et al. (2004). Oxi-
dized galectin-1 stimulates macrophages to promote axonal regeneration in peripheral
nerves after axotomy. The Journal of Neuroscience,24(8), 1873–1880.
Hughes, P. M., & Perry, V. H. (2000). The role of macrophages in degeneration and regen-
eration in the peripheral nervous system. In N. Saunders, K. M. Dzieqielewska, &
N. R. Saunders (Eds.), Degeneration and regeneration in the nervous system (pp. 263–283).
The Netherlands: Harwood Academic.
Hunt, D., Hossain-Ibrahim, K., Mason, M. R., Coffin, R. S., Lieberman, A. R.,
Winterbottom, J., et al. (2004). ATF3 upregulation in glia during Wallerian degenera-
tion: Differential expression in peripheral nerves and CNS white matter. BMC Neurosci-
ence,4(5), 9.
Kuo, Y. R., Wang, C. T., Wang, F. S., Yang, K. D., Chiang, Y. C., & Wang, C. J. (2009).
Extracorporeal shock wave treatment modulates skin fibroblast recruitment and leuko-
cyte infiltration for enhancing extended skin-flap survival. Wound Repair and Regenera-
tion,17, 80–87.
Lefcort, F., Venstrom, K., McDonald, J. A., & Reichardt, L. F. (1992). Regulation of expres-
sion of fibronectin and its receptor, alpha 5 beta 1, during development and regeneration
of peripheral nerve. Development,116(3), 767–782.
Low, H. L., No
´gra
´di, A., Vrbova
´, G., & Greensmith, L. (2003). Axotomized motoneurons
can be rescued from cell death by peripheral nerve grafts: The effect of donor age. Journal
of Neuropathology and Experimental Neurology,62(1), 75–87.
Mariotto, S., Carcereri de Prati, A., Cavalieri, E., Amelio, E., Marlinghaus, E., & Suzuki, H.
(2009). Extracorporeal shock wave therapy in inflammatory diseases: Molecular mech-
anism that triggers anti-inflammatory action. Current Medicinal Chemistry,16,
2366–2372.
Martini, L., Giavaresi, G., Fini, M., Torricelli, P., de Pretto, M., Schaden, W., et al. (2003).
Effect of extracorporeal shock wave therapy on osteoblast like cells. Clinical Orthopaedics
and Related Research,413, 269–280.
Mittermayer, R., Antonic, V., Hartinger, J., Kaufmann, H., Redl, H., Te
´ot, L., et al. (2012).
Extracorporeal shock wave therapy (ESWT) for wound healing: Technology, mecha-
nisms, and clinical efficacy. Wound Repair and Regeneration,20, 456–465.
Murata, R., Ohtori, S., Ochiai, N., Takahashi, N., Saisu, T., Moriya, H., et al. (2006). Extra-
corporeal shockwaves induce the expression of ATF3 and GAP-43 in rat dorsal root gan-
glion neurons. Autonomic Neuroscience,128(1–2), 96–100.
Nishida, T., Shimokawa, H., Oi, K., Tatewaki, H., Uwatoku, T., Abe, K., et al. (2004).
Extracoporeal cardiac shock wave therapy ameliorates markedly ameliorates ischemia-
induced myocardial dysfunction pigs in vivo. Circulation,110, 3055.
97The Use of Shock Waves in Peripheral Nerve Regeneration: New Perspectives?
Author's personal copy
Ogden, J. A., Alvarez, R., Levitt, R., Cross, G. L., & Marlow, M. (2001). Shockwave ther-
apy for chronic proximal plantar fasciitis. Clinical Orthopaedics and Related Research,387,
47–59.
Ohtori, S., Inoue, G., Mannoji, C., Saisu, T., Takahashi, K., Mitsuhashi, S., et al. (2001).
Shock wave application to rat skin induces degeneration and reinnervation of sensory
nerve fibres. Neuroscience Letters,315(1–2), 57–60.
Orr, A. W., Helmke, B. P., Blackmann, B. R., & Schwartz, M. A. (2006). Mechanisms of
mechanotransduction. Developmental Cell,10, 11–20.
Sadoun, E., & Reed, M. J. (2003). Impaired angiogenesis in aging is associated with alter-
ations in vessel density, matrix composition, inflammatory response, and growth factor
expression. The Journal of Histochemistry and Cytochemistry,51, 1119–1130.
Saito, H., & Dahlin, L. B. (2008). Expression of ATF3 and axonal outgrowth are impaired
after delayed nerve repair. BMC Neuroscience,9, 88.
Schaden, W., Thiele, R., Kolpl, C., Pusch, M., Nissan, A., Attinger, C. E., et al. (2007).
Shock wave therapy for acute and chronic soft tissue wounds: A feasibility study. The
Journal of Surgical Research,143, 1–12.
Shrivastava, S. K., & Kailash, S. K. (2005). Shock wave treatment in medicine. Journal of Bio-
sciences,30(2), 269–275.
Stojadinovic, A., Elster, E. A., Anam, K., Tadaki, D., Amare, M., Zins, S., et al. (2008).
Angiogenic response to extracorporeal shock wave treatment in murine skin isografts.
Angiogenesis,11, 369–380.
Stoll, G., & Mu
¨ller, H. W. (1999). Nerve injury, axonal degeneration and neural regener-
ation: Basic insights. Brain Pathology,9(2), 313–325.
Takahashi, N., Ohtori, S., Saisu, T., Moriya, H., & Wada, Y. (2006). Second application of
low-energy shock waves has a cumulative effect on free nerve endings. Clinical Orthopae-
dics and Related Research,443, 315–319.
Thiel, M. (2001). Application of shock waves in medicine. Clinical Orthopaedics and Related
Research,387, 18–21.
Tinazzi, E., Amelio, E., Marangoni, E., Guerra, C., Puccetti, A., Codella, O. M., et al.
(2011). Effects of shock wave therapy in the skin of patients with progressive systemic
sclerosis: A pilot study. Rheumatology International,31(5), 651–656.
Tomaselli, K. J., Doherty, P., Emmett, C. J., Damsky, C. H., Walsh, F. S., & Reichardt, L. F.
(1993). Expression of beta 1 integrins in sensory neurons of the dorsal root ganglion and
their functions in neurite outgrowth on two laminin isoforms. The Journal of Neuroscience,
13(11), 4880–4888.
Wang, F. S., Wang, C. J., Chen, Y. J., Chang, P. R., Huang, Y. T., Sun, Y. C., et al. (2004).
Ras induction of superoxide activates ERK-dependent angiogenic transcription factor
HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. The Journal
of Biological Chemistry,279, 10331–10337.
Wu, Y. H., Lun, J. J., Chen, W. S., & Chong, F. C. (2007). The electrophysiological and
functional effect of shock wave on peripheral nerves. Conference Proceedings—IEEE
Engineering in Medicine and Biology Society, 2369–2372.
Yan, X., Zeng, B., Chai, Y., Luo, C., & Li, X. (2008). Improvement of blood flow, expres-
sion of nitric oxide, and vascular endothelial growth factor by low-energy shockwave
therapy in random-pattern skin flap model. Annals of Plastic Surgery,61, 646–653.
Zimpfer, D., Aharinejad, S., Holfeld, J., Thomas, A., Dumfarth, J., Rosenhek, R., et al.
(2009). Direct epicardial shock wave therapy improves ventricular function and induces
angiogenesis in ischemic heart failure. The Journal of Thoracic and Cardiovascular Surgery,
137, 963–970.
98 Thomas Hausner and Antal Nógrádi
Author's personal copy
