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Rola, P. Clinical Applications of Shock Wave. Encyclopedia. Available online: https://encyclopedia.pub/entry/20683 (accessed on 27 July 2024).
Rola P. Clinical Applications of Shock Wave. Encyclopedia. Available at: https://encyclopedia.pub/entry/20683. Accessed July 27, 2024.
Rola, Piotr. "Clinical Applications of Shock Wave" Encyclopedia, https://encyclopedia.pub/entry/20683 (accessed July 27, 2024).
Rola, P. (2022, March 17). Clinical Applications of Shock Wave. In Encyclopedia. https://encyclopedia.pub/entry/20683
Rola, Piotr. "Clinical Applications of Shock Wave." Encyclopedia. Web. 17 March, 2022.
Clinical Applications of Shock Wave
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10030568

Shock Waves (SW) are acoustic disturbances that propagate through a medium carrying the energy. These specific sonic pulses are composed of two phases—high positive pressure, a rise time < 10 ns, and a tensile wave. 

shockwave shock wave therapy clinical application mechanism of action medicine treatment technique

1. Urology

The first implemented and well-established clinical application of ShockWave Technology was the low-invasive destruction of kidney stones [1]. In the 40 years following the invention of Extracorporeally Shock Wave Lithotripsy (ESWL) it has become the procedure of choice for most renal calculi. The mechanism of kidney stone disintegration is closely related to the physical effects of shockwaves on calcified structures. Despite the long history of ESWL use, there are still some concerns about the side effects of this procedure. It has been proven that renal cells injury provoked by ESWL is not only connected with mechanical trauma [2][3][4]. The exact mechanism of this phenomenon remains unclear. Munver et al. [5] associated early renal injury after ESWL with excessive production of Reactive Oxygen Spices (ROS), but on the other hand, Sonden et al. [6] postulated it was independent from the ROS mechanism of cell destruction. In turn, both the early and late damage mechanism are strongly connected with an inflammatory response to ESWL with secondary intensification of fibrotic processes. This process is closely associated with inflammatory factors. The activation of Intercellular Adhesion Molecule1 (ICAM-1), Tumor necrosis factor-α (TNF-α), and Interleukin 6 (IL-6) are postulated to play a crucial role in the early stage. While monocyte chemoattractant protein-1 (MCP-1) and IL-18 may respond to the long-term renal damage [4]. Although these are not the only molecules responsible for post ESWL chronic renal impairment.
This process is related to NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity [7]. NFκB is a transcription factor playing an important role in the etiopathogenesis of chronic inflammatory or fibrosis diseases, due to the ability to induce transcription of fibrotic genes [8]. ESWL-related renal damage is not only connected with ROS and inflammatory process. It has also been proven that SW affects viability by activating the apoptotic cell death signaling pathway [9]. Notably, ESWL has a divergent action; it can also activate autophagy-self-protective cellular response reducing injury of renal tubular epithelial cells. Cytoprotection of autophagy seems to be dependent on the ability to regulate the Akt/GSK-3β pathway, which affects cell survival under conditions of oxidative stress.
Besides the therapy of kidney stones, shock waves a reused in the treatment of erectile dysfunction (ED) [10]. There is a strong piece of evidence suggesting the clinical effectiveness of this therapy in the group with varying severities of the disease [11]. There are many potential mechanisms responsible for this biological effect. Li et al. [12] postulated that low energy shock wave therapy can increase cell proliferation, tissue regeneration, nerve generation, and angiogenesis in a rat model of pelvic neurovascular injuries. In the process of re-innervation of penile tissue with coexisting regeneration of neuronal nitric oxide synthase (nNOS), Schwann cells are involved.
Enhanced cell activity and proliferation is achieved by the upregulation of specific markers including p-Erk1/2 and p75. Similar increasing activity of neuronal nitric oxide synthase (nNOS) was observed by Qiu et al. [13]. They postulated that SW therapy can partially resolve diabetes mellitus-associated ED by promoting nerve regeneration due to the increased synthesis of nitric oxide.
Anti-inflammatory and analgesic properties of SWT have been also applied in other fields of urology. Recent data suggest that SWT may exert a therapeutic effect in non-bacterial prostatitis. Wang et al. [14] suggest that low-energy shock wave therapy has the ability to suppress the expression of the pro-inflammatory molecules, interleukin 1β (IL-1β), cyclooxygenase- 2 (COX-2), caspase-1, Nerve growth factor (NGF), and Tumor Necrosis Factor-α (TNF-α).

2. Orthopedics

The first well-proven indication of SW therapy in orthopedics was management of tendonitis. ESWs devices have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of plantar fasciitis including Achilles’ tendon diseases. The effectiveness and safety of this application of SW had been confirmed in numerous randomized trials [15][16]. The mechanism of action in connective tissue diseases requires further investigation. Briefly, one of the postulated therapeutic mechanisms is the modification of the immune response—by shifting polarity in the macrophage phenotype from M1 to M2 [17]. As a general rule, the M1 population of macrophages is responsible for the pro-inflammatory response, they play an important role in the direct host-defense against pathogens such as phagocytosis and secretion of the pro-inflammatory cytokines and microbicidal molecules. On the other hand, the group of M2 macrophages limits the immune response and intensifies anti-inflammatory properties [18]. The type 2 response is known to be directly involved in regenerative processes (cell proliferation, and polyamine and collagen synthesis, releasing IL-10, and IL-4) and the promotion of angiogenesis through the release of various cytokines and growth factors. Data from animal models confirm an increase in neo-angiogenesis after shockwave therapy. Wang et al. [19][20] suggest that application of Extracorporeally Shock Wave Therapy (ESWT) caused an increasing number of neo-vessels as well as enhanced release growth and neovascularization markers including vascular endothelial growth factor (VEGF), eNOS, proliferating cell nuclear antigen (PCNA), and the bone morphogenic protein-2 (BMP-2).
ESWT accelerates the healing of tendon pathologies not only by modulating the immune response by vascular proliferation, but also by direct influence on human tenocytes. Vetrano et al. [21] showed up that Extracorporeal shock wave therapy promoted cell proliferation and changes in cell morphology and dedifferentiation. It was suggested that this effect was supported by a significant increase in the levels of the Ki67 proliferation marker. Another postulated mechanism of tendinopathy was suggested by Han et al. [22] who found higher levels of matrix metalloproteinases-1, -2, and -13 (MMP-1, -2, and-13) and IL- 6 in human tendinopathy-affected tenocytes as compared with normal cells. What is interesting, the ESWT managed to reverse an unfavorable attitude and decreased the expression of several MMPs and IL-6. Enhancement of proliferation might relate to the increased level of extracellular adenosine triphosphate (ATP) after shock wave therapy, it was proven that it can trigger the release of ATP, thereby activating theErk1/2 and p38 MAPK signaling pathways.
Pain relief is also an important part of therapy in various tendinopathies. As the it was suggested [23][24], ESWT might have analgesic properties. At the heart of these processes seems to involve changes in tissue concentrations of substance P and prostaglandin E2 [25]. The function of joint tendons can be improved by another kind of mechanism, ESWT can stimuli the synthesis of lubricin. This glycoprotein substance is important particularly for the tendon structures, because it facilitates tracking of the tendons. This effect can be achieved by modulation the expression of TGF-b1 [26].

3. Cardiology

Due to numerous studies conducted on animal models and human experimental trials with the shock wave therapy, new therapeutic applications in cardiology are being discovered and enrolled in clinical practice. At the beginning, in the cardiology field, extracorporeal shock waves were tested in the porcine model of ischemic cardiomyopathy. Nishida et al. [27] have proven that SW therapy might be asafe and an effective therapeutic strategy for coronary artery disease. They showed significant improvement in recovery of left ventricular ejection fraction, wall thickening fraction, and myocardial regional blood flow. They associate the observed effects with up-regulation in the synthesis of vascular endothelial growth factor (VEGF). A similar effect in the prevention of early ischemic left ventricular remodeling by SWT was observed by Uwatoku et al. [28]. The exact mechanism of these changes remains unclear. Most of the available studies point to the influence on angiogenesis as a possible mechanism of action. Tepekoylu et al. [29] suggested that increased vascular formation might be mediated via RNA/protein complexes with involvement of the antimicrobial peptide LL37 activating TLR3 (Toll-like receptor 3). A completely different mode of healing action of SWT in human heart failure is presented by Assmus et al. [30] They examined the effect of intracoronary administration of autologous bone marrow-derived mononuclear cells in subjects with post-infarction chronic heart failure (HFrEF, heart failure with reduced ejection fraction). Additionally, one of the groups received the subsequent application of SWT. As a result, post shock wave group-facilitated intracoronary administration of bone marrow-derived mononuclear cells led to a significant improvement in the left ventricular ejection fraction. Authors postulated a connection between the extracorporeal application of low-energy shock waves and increased expression of chemoattractant such as stromal cell-derived factor 1 (SCDF-1) and VEGF in the target tissues. Notably, the authors claim that pure shock therapy (without administration of autologous bone marrow-derived mononuclear cells) did not result in any improvement in cardiac muscle function.
There are few clinical studies focused on the influence of SWT on patients with chronic refractory angina [31][32][33]. Vainer et al. [32] proven that cardiac shockwave therapy improved symptoms and reduced ischemia burden in patients with end-stage coronary artery disease. They investigated the clinical response of 33 humans on the 4-month outpatient shockwave treatment protocol. It was found that SWT reduced the use of sublingual nitrates and decreased angina complaints (at least one CCS class). What was most encouraging was that they noticed a significant decrease in ischemia burden in the treated regions, as assessed using SPECT stress images. This might suggest that at least a part of the positive effect is correlated with improved perfusion in the treated ischemic zones. More details regarding the molecular mechanism of this phenomenon are highlighted in a paper by Chai et al. [34], which postulates that one of the mechanisms involved in the SWT anti-ischemic model of action could rely on neovascularization and increase the number and activation of circulating endothelial progenitor cells. The authors suggest that higher levels of IL-8 and VEGF are mediators of these processes.

4. Dermatology

Among all the clinical applications of the shock wave in dermatology, the ability to enhance tissues regeneration is most often applied. Several studies have assessed the effectiveness and safety of shockwave therapy in the treatment of patients with chronic leg ulcers [35][36][37][38][39]. Chronic foot ulcers are defined as non-healing ulcers with a duration time of at least 3months. The etiology of such ulcers is diversified. Conventionally they can be divided into two main groups: diabetic and non-diabetic. Non-diabetic ulcers are caused by peripheral arterial disease, post-traumatic skin lesions, infections, deep vein thrombosis, or venous stasis with poor venous return. Managements of chronic foot ulcers require multidisciplinary approaches such as wound care, surgery, antibiotics, diabetic control, or compression therapy [37]. However, sometimes it is insufficient, and alternative therapy such as oxygen, larvae, or laser radiation therapy is needed. Wang et al. [38] showed that extracorporeal shockwave therapy (ESWT) is effective and safe in the treatment of chronic foot ulcers in short- and long-term therapy. They reported better clinical results in the non-diabetic group than the opposite one. Despite all the differences, both groups achieve long-term improvement. The authors combine the positive results with significant improvement in blood flow perfusion rate in the treated skin area. The exact mechanism of ESWT remains unclear but data from animal experiments [21][22][38][40] suggest that SWT could up-regulate angiogenic and osteogenic growth factors: endothelial nitric oxide synthase, vascular endothelial growth factor, bone morphogenetic protein 2, and proliferating cell nuclear antigen.
Not only ulcers are in the spotlight of Shockwave therapy in dermatology. Schaden et al. [41] tested the use of unfocused, low-energy ESWT on a large population of patients with acute or chronic soft tissue wounds. This registry indicates that shock wave therapy is safe and effective in “real life, everyday practice”. They postulated several benefits of SWT including ease of application, minimally invasive, low-profile side-effect, and painlessness (patients do not require additional anesthetics).
Hypertrophic and contracture scars after burn injuries can cause functional and cosmetic deformities. Fioramonti et al. [42] observed improvement in scar appearance after application of SW in postburn pathologic scars. The explanation for the clinical benefits of ESWT is probably changing the expression of fibrosis-related molecules in fibroblasts. To examine these phenomena, Cui et al. [43] derived fibroblasts from human hypertrophic scars and investigated the influent of shockwave therapy on them. They demonstrated that ESWT did not have any impact on the viability of fibroblasts, but it decreased migration as well as inhibited expression of transforming growth factor-beta 1 (TGF-β1), alpha-smooth muscle actin (α-SMA), collagen-I, fibronectin, and twist-1. They noticed increased expression of E-cadherin with coexisting reduction in N-cadherin. In conclusion, they put forward a proposal that suppressed epithelial–mesenchymal transition might be responsible for the anti-scarring effect of ESWT and is a potential therapeutic target in the management of post-burn scars.

5. Neurology

Stroke is, now a days, among the leading causes of disability. Numerous patients who experienced stroke have decreased health-related quality of life, mainly due to the presence of spasticity. Despite various proposed treatments (invasive and non-invasive), spasticity remains a burning clinical problem. A growing amount of evidence [44][45] suggests the usefulness of ESWT in neurological conditions. Particularly in the therapy of post-stroke muscle spasticity [46]. Furthermore, shockwave therapy is effective alone and as a support of conventional physiotherapy or botulinum toxin. Studies conducted so far suggest that ESWT affects the rheological properties of the spastic muscle. The mechanism of action is based on intrinsic hypertonia or spasticity. Notably, no major complications or side effects occur after the treatment, as reported in the previously mentioned meta-analysis.
Since conventional treatments for postherpetic neuralgia (PHN) and postherpetic itch (PHI) are insufficient, novel therapeutic methods are urgently needed. Lee et al. [47] postulated that ESW has the ability to decrease significantly PHN and PHI. Unfortunately, the exact mechanism of this process remains unclear.
Post-herpetic neuralgia is not the only neurological condition where analgesic properties of ESW are used. Low back pain (LBP) is one of the leading causes of chronic pain worldwide, generating significant costs for the healthcare system. Walewicz et al. [48] conducted a randomized clinical trial, which suggests that ESWT can have a long-term impact on reducing chronic low back pain and may lead to significant improvement in the postural sway in patients with LBP compared with standard core stability training.
Since Shock Wave Therapy shows the ability to enhance metabolic activity and increase the proliferation potential of various cells, regenerative properties of SWT have been used to promote peripheral nerve regeneration [49][50]. Li et al. [50] showed a post-SWT significant promotion of axonal regrowth and increased myelination expression, where the potential molecular mechanism is related to increased expression of two mechanosensitive transcription factors YAP/TAZ proteins. Regenerative and neuroprotection properties of SWT have been applied in spinal cord injury models. Lobenwein et al. [51] along with Gollmann-Tepeköylü [52] indicate that Toll-like receptor (TLR) 3 signaling is involved in neuroprotection and spinal cord repair. Additionally, vascular endothelial growth factor (VEGF) [53] related mechanisms are postulated to be involved in this process. Moreover, since SWT can activate stem cells [54][55][56], along with the ongoing development of this treatment method, a potentially wide range of applications in the different fields of regenerative medicine can be applied [57][58][59][60]—not only those related to the central or peripheral nervous system.

References

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Subjects: Medicine, Research & Experimental
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Piotr Rola
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