Abstract
Background
As there is no consensus over the efficacy of extracorporeal shockwave therapy in the management of spinal cord injury complications, the current meta-analysis aims to investigate preclinical evidence on the matter.
Methods
The search strategy was developed based on keywords related to ‘spinal cord injury’ and ‘extracorporeal shockwave therapy’. A primary search was conducted in Medline, Embase, Scopus and Web of Science until the end of 2020. Studies which administered extracorporeal shockwave therapy on spinal cord injury animal models and evaluated motor function and/or histological findings were included. The standardised mean difference with a 95% confidence interval (CI) were calculated.
Results
Seven articles were included. Locomotion was significantly improved in the extracorporeal shockwave therapy treated group (standardised mean difference 1.68, 95% CI 1.05–2.31, P=0.032). It seems that the efficacy of extracorporeal shockwave therapy with an energy flux density of 0.1 mJ/mm2 is higher than 0.04 mJ/mm2 (P=0.044). Shockwave therapy was found to increase axonal sprouting (standardised mean difference 1.31, 95% CI 0.65, 1.96), vascular endothelial growth factor tissue levels (standardised mean difference 1.36, 95% CI 0.54, 2.18) and cell survival (standardised mean difference 2.49, 95% CI 0.93, 4.04). It also significantly prevents axonal degeneration (standardised mean difference 2.25, 95% CI 1.47, 3.02).
Conclusion
Extracorporeal shockwave therapy significantly improves locomotor recovery in spinal cord injury animal models through neural tissue regeneration. Nonetheless, in spite of the promising results and clinical application of extracorporeal shockwave therapy in various conditions, current evidence implies that designing clinical trials on extracorporeal shockwave therapy in the management of spinal cord injury may not be soon. Hence, further preclinical studies with the effort to reach the safest and the most efficient treatment protocol are needed.
Keywords: Extracorporeal shockwave therapy, spinal cord injuries, locomotion, regeneration
Introduction
Spinal cord injury (SCI) is among the most common accidental injuries with no definite cure yet. 1 In mild injuries patients’ sensation and motor function could be desirably retained through decompression surgery, corticosteroid prescription and rehabilitation.1,2 However, in moderate to severe injuries, tissue damage is to such an extent that a cascade of destructive mechanisms is activated, which leads to apoptosis, axonal degeneration and eventually, motor and sensation dysfunction. 3
Although there is no efficient treatment for moderate to severe SCI, researchers have introduced several treatments including cell therapy, gene therapy, etc., with most of them being preclinical studies,4–6 and few of them at phase I or II clinical trials. Nevertheless, all of these methods have several limitations, and their side effects have not yet been fully recognised.7–9 For instance, stem cell transplantation is a promising method for the successful regeneration of the spinal cord damaged tissue, and several preclinical studies have revealed its positive and significant effects.10–12 However, considerations about tumorigenesis present a barrier to its extensive application.
To overcome these limitations, finding a non-invasive technique to stimulate endogenous stem cells to proliferate and differentiate would be ideal. Using extracorporeal shock wave therapy (ESWT), after SCI, has been proposed to be efficient in several studies. 13 Shockwave therapy is a non-invasive method, which is well established for pain management and improving muscle strength in the clinic. The shockwaves are rapid fluctuations of pressure which stimulate the tissue mechanically. 14 Studies show that ESWT promotes axonal regeneration and stimulates angiogenesis. All of these mechanisms could lead to an improvement of locomotion and sensation. 13 , 15
Nonetheless, there is no consensus over the efficacy of ESWT in the management of SCI complications. Moreover, the effect of wave intensity and factors related to SCI (location of injury, severity of injury, etc.) on the efficacy of the treatment have not yet been fully investigated. Thus, the current meta-analysis aims to investigate the efficacy of ESWT on the management of SCI complications.
Methods
Study design
The PICO of current study was defined as follows: problem (P): animals (rats or mice) subjected to SCI; intervention (I): low-energy ESWT; comparison (C): non-treated SCI animals; outcome (O): locomotion and histological findings.
Search strategy
The search strategy was developed based on keywords related to ‘spinal cord injury’ and ‘extracorporeal shockwave therapy’. A primary search was conducted in Medline, Embase, Scopus and Web of Science until the end of 2020. The search query in PubMed is presented in Appendix 1. The bibliographies of related articles and reviews were also investigated for additional records. Grey literature was achieved through search in ProQuest, Google Scholar and Google motor engine.
Selection criteria
The records which administered ESWT on animals subjected to SCI and evaluated the motor function and/or histological findings were included. Review articles, not having a non-treated group, not evaluating the motor or histological outcome, lack of details on the administration method and retraction of the articles were defined as the exclusion criteria.
Data extraction and quality assessment
Duplicate articles were eliminated after conducting the search in all the four online databases. The obtained records were then provided to two independent researchers for the initial screening, which was done by studying the titles and abstracts of the articles. Afterwards, the full texts of potentially relevant papers were assessed carefully and related articles were included. The data of these records were summarised in a checklist designed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. This checklist consisted of the following variables: study characteristics, the species, age, and sex of the animals, the model of SCI induction, interval time from SCI to treatment, energy flux density, frequency, and follow-up time. The results of the last follow-up time were included. As most of the animal studies report their results in figures, the data were extracted by using Plot Digitizer software. Any disagreement in any of the afore-mentioned steps was resolved through discussion with a third researcher. Quality assessment of the articles was done by the guideline proposed by the SYRCLE guideline. 16
Statistical analysis
The data were recorded as mean, standard deviation and the sample size of each group in STATA 14.0 statistical program. By calculating the standardised mean difference (SMD) with a 95% confidence interval (CI) by using the ‘metan’ command, a pooled SMD was then reported. Heterogeneity between the studies was evaluated by performing the I2 test. As a moderate heterogeneity was observed among the studies, subgroup analysis was conducted to determine the sources of this heterogeneity. A funnel plot was applied to identify publication bias using Egger’s tests. 17
Results
Study characteristics
The titles and abstracts of 158 non-duplicate papers were screened and then the full texts of 14 articles were selected as eligible for in-depth assessment. Finally, the data of the seven studies were included, containing nine separate experiments 15 ,18–22 (Figure 1). Six studies used the compression/contusion model to induce SCI. The severity of injury was moderate in all experiments. The location of injury was in the thoracic region in all of the studies. Low-energy ESWT was implemented in the experiments, with energy levels of 0.04, 0.1, 0.25 mJ/mm2, and the frequency was 4 or 5 Hz among all the studies (Table 1).
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the present study.
Table 1.
Characteristics of included studies.
| Author, year | Gender; species; species cat; strain; weight | Model; method of injury; severity of injury; injury location | Sample size (SCI/ treat) | Number of shot/number of impulses per shot/energy flux density (mJ/mm2)/ frequency (Hz)/interval time injury to treat (day) | Outcome | Follow-up duration (weeks) |
|---|---|---|---|---|---|---|
| Gollmann-Tepeköylü, 2020 | Male; mice; 2; C57BL/6; 18–25 | Compression; moderate; T9 | 4/6 | 1/500/0.1/5/14 | Motor function; axonal degeneration | 10 |
| Lee, 2014 | Male; rat; 1; Sprague–Dawley; 290–340 | Contusion; moderate; T9 | 9/9 | 1/1000/0.04/99/28 | Motor function; axonal sprouting; VEGF | 10 |
| Lobewein, 2015 | Male; mice; 2; C57BL/6; 25–30 | Ischaemic; moderate; Global | 6/6 | 1/500/0.1/5/0 | Motor function; axonal degeneration; VEGF | 1 |
| Matsuda, 2020 | Female; rat; 1; Sprague–Dawley; 250–300 | Contusion; moderate; T10 | 5/5 | 6/400/0.25/4/0 | Motor function | 3 |
| Shin, 2017 | N/A; rat; 1; Sprague–Dawley; N/A | Contusion; 10 g, 2.5 cm; moderate; T9 | 6/18 | 1/500, 1000, 1500/0.04/ 99/28 | Motor function; axonal sprouting | 10 |
| Yahata, 2016 | Female; rat; 1; Sprague–Dawley; 250–300 | Contusion; moderate; T10 | 10/10 | 9/400/0.25/4/0 | Motor function; axonal degeneration; cell survival | 6 |
| Yamaya, 2016 | Female; rat; 1; Sprague–Dawley; 250–300 | Contusion; moderate; T11 | 10/10 | 9/400/0.25/4/0 | Motor function; axonal degeneration; VEGF; cell survival | 6 |
SCI: spinal cord injury; VEGF: vascular endothelial growth factor.
Risk of bias assessment
Quality assessment revealed that all of the included studies had a low risk of bias on items of sequence generation, baseline characteristics and other sources of bias. However, the risk of bias was high or unclear on random housing and random outcome assessment items in all of the studies. In four of the articles, the caregivers and/or investigators were not blinded and, hence, allocation concealment was not properly conducted. Only two studies had a low risk of bias on incomplete outcome data reporting and the risk of bias could not be assessed in any of the studies on selective outcome reporting (Table 2).
Table 2.
Risk of bias assessment of included studies.
| Study | Sequence generation | Baseline characteristics | Allocation concealment | Random housing | Caregivers and/or investigators blinding | Random outcome assessment | Outcome assessor blinding | Incomplete outcome data | Selective outcome reporting | Other sources of bias |
|---|---|---|---|---|---|---|---|---|---|---|
| Gollmann-Tepeköylü, 2020 | Low | Low | High | High | High | High | Low | Unclear | Unclear | Low |
| Lee, 2014 | Low | Low | High | High | High | High | High | Unclear | Unclear | Low |
| Lobewein, 2015 | Low | Low | Low | Unclear | Low | Unclear | Low | Low | Unclear | Low |
| Matsuda, 2020 | Low | Low | Low | Unclear | Low | Unclear | Low | Unclear | Unclear | Low |
| Shin, 2017 | Low | Low | High | High | High | High | High | Unclear | Unclear | Low |
| Yahata, 2016 | Low | Low | Low | Unclear | Low | Unclear | Low | Unclear | Unclear | Low |
| Yamaya, 2016 | Low | Low | Low | Unclear | Low | Unclear | Low | Low | Unclear | Low |
Publication bias
No significant publication bias was observed regarding locomotion, axonal degeneration, axonal sprouting and vascular endothelial growth factor (VEGF) assessment. As only two articles had reported results on cell survival, the publication bias could not be evaluated in this section (Figure 2).
Figure 2.
Publication bias assessment across included studies. SE: standard error; VEGF: vascular endothelial growth factor.
The efficacy of administration of ESWT on locomotion
The locomotion in the ESWT treated group was significantly improved compared to non-treated animals (SMD 1.68, 95% CI 1.05–2.31, P=0.032). The I2 test revealed a moderate heterogeneity of 52.2% between the studies (Figure 3). Subgroup analysis was performed to find the sources of this heterogeneity. The findings showed species to be one of the possible sources of the heterogeneity. The I2 test in rat studies revealed heterogeneity to be 48.2% while this was 0.00% in mouse studies. Shockwave therapy was effective in improving motor function in both of the species (P=0.111).
Figure 3.
Forest plot of extracorporeal shockwave therapy (ESWT) administration effect on improvement of locomotor function. CI: confidence interval; SMD: standardised mean difference.
The number of impulses (frequency) was also a possible source of heterogeneity among the studies. Heterogeneity among the studies, which used less than 500 impulses and more than 500 impulses, was 37.8% and 0.0%, respectively. Both over and under 500 impulses enhance motor recovery (P=0.066). In addition, heterogeneity among studies in which they used energy flux density 0.04 mJ/mm2 and 0.1 mJ/mm2 was 0.0%. It seems that the efficacy of ESWT with an energy flux density of 0.1 mJ/mm2 is higher than 0.04 mJ/mm2 (P=0.044). Other sources of heterogeneity were frequency of impulses, interval time from SCI to treatment and follow-up duration (Table 3).
Table 3.
Subgroup analysis of ESWT effect on motor function recovery after spinal cord injury compared to non-treated animals.
| Subgroup | No. of studies | Heterogeneity (P value) | SMD (95% CI) | P value | Coefficient (95% CI) | P value |
|---|---|---|---|---|---|---|
| Species | ||||||
| Rat | 7 | 48.6% (0.070) | 2.91 (1.63, 4.18) | <0.001 | 1 | |
| Mice | 2 | 0.0% (0.932) | 1.44 (0.80, 2.07) | <0.001 | 1.48 (–0.44, 3.41) | 0.111 |
| SCI model | ||||||
| Contusion/compression | 8 | 50.9% (0.047) | 1.56 (0.92, 2.20) | <0.001 | 1 | |
| Ischaemia | 1 | – | 2.86 (1.17, 4.55) | 0.001 | 1.30 (1.39, 3.98) | 0.291 |
| No. of impulses | ||||||
| <500 | 6 | 37.8% (0.154) | 2.12 (1.39, 2.85) | <0.001 | 1 | |
| ≥500 | 3 | 0.0% (0.417) | 0.85 (0.21, 1.50) | 0.009 | –1.20 (–2.50, 0.10) | 0.066 |
| Energy flux density (mJ/mm2) | ||||||
| 0.04 | 4 | 0.00% (0.571) | 0.93 (0.36, 1.50) | 0.001 | 1 | |
| 0.1 | 2 | 0.00% (0.932) | 2.91(1.64, 4.18) | <0.001 | 1.95 (0.07, 3.82) | 0.044 |
| 0.25 | 3 | 56.1% (0.102) | 2.13 (1.00, 3.26) | <0.001 | 1.08 (–0.23, 2.34) | 0.090 |
| Frequency (Hz) | ||||||
| 4 | 3 | 56.1% (0.102) | 2.13 (1.00 ,3.26) | <0.001 | ||
| 5 | 2 | 0.00% (0.932) | 2.91 (1.64, 4.18) | <0.001 | 0.87 (–1.10, 2.84) | 0.322 |
| Not reported | 4 | 0.00% (0.571) | 0.93 (0.36, 1.50) | 0.001 | –1.08 (–2.40, 0.23) | 0.090 |
| Interval time from SCI to treatment | ||||||
| Acute/subacute (immediate) | 4 | 44.9% (0.142) | 2.26 (1.33, 3.18) | <0.001 | 1 | |
| Chronic (14–28 days) | 5 | 32.9% (0.202) | 1.18 (0.49, 1.87) | 0.001 | –1.03 (2.39,0.33) | 0.116 |
| Follow-up weeks | ||||||
| <4 weeks | 2 | 0.0% (0.613) | 2.55 (1.37, 3.73) | <0.001 | 1 | |
| ≥4 weeks | 7 | 54.7% (0.039) | 1.50 (0.81, 2.19) | <0.001 | –1.07 (–3.02, 0.88) | 0.238 |
| Overall | 9 | 52.2% (0.032) | 1.68 (1.05, 2.31) | <0.001 | – | – |
CI: confidence interval; SCI: spinal cord injury; SMD: standardised mean difference.
The efficacy of administration of ESWT on histological findings
Shock wave therapy was found to increase axonal sprouting (SMD 1.31, 95% CI 0.65, 1.96), VEGF tissue levels (SMD 1.36, 95% CI 0.54, 2.18) and host tissue cell survival (SMD 2.49, 95% CI 0.93, 4.04). It also significantly prevents axonal degeneration (SMD 2.25, 95% CI 1.47, 3.02). No heterogeneity was observed regarding the changes in axonal degeneration (I2=41.8%) and axonal sprouting (I2=41.8%). Meanwhile, moderate heterogeneity was seen among the articles reporting VEGF tissue level changes (I2=50.2%). Heterogeneity could not be assessed among articles reporting host tissue cell survival, because only two articles reported this outcome (Figure 4).
Figure 4.
Forest plot of extracorporeal shockwave therapy (ESWT) administration effect on histological findings. CI: confidence interval; SMD: standardised mean difference; VEGF: vascular endothelial growth factor.
Discussion
In spite of growing research on stem cell therapy for the treatment of SCI, discovering a strategy, with the goal of endogenous stem cell proliferation and differentiation, would be ideal to overcome the limitations of the exogenous transplantation of stem cells. In the current study, the research performed a meta-analysis on the current data with the aim of answering the question whether or not ESWT could improve locomotion and tissue regeneration of animals subjected to SCI. The findings demonstrated that low-energy ESWT significantly improves locomotion in animals subjected to SCI. Moreover, the analysis showed that this modality is significantly effective in preventing axonal degeneration and increasing cell survival, axonal sprouting and VEGF expression in the injured spinal cord. A concise illustration of the findings is presented in Figure 5. These histological findings may explain the mechanisms by which ESWT restores motor function after the injury. A moderate heterogeneity was observed among the studies. Subgroup analysis indicated that the main source of this heterogeneity was the species of animals, model of injury, energy levels and number of impulses.
Figure 5.
Findings of the current study. VEGF: vascular endothelial growth factor.
The results also showed that an energy flux density of 0.1 mJ/mm2 was more efficient than 0.04 and 0.25 mJ/mm2 in improving locomotion recovery. Energy level is an important factor, which could considerably affect the clinical outcome following ESWT application, as high energy ESWT has been reported not only to repair but also damage the neural tissue. For instance, energy flux density of 0.49 mJ/mm2 was shown to cause soft tissue damage and ischaemia. 23 In another preclinical study conducted on rabbits, the application of 0.9 mJ/mm2 ESWT was found to reduce the number of neurons in dorsal root ganglia. 24 As a result, providing accurate protocols might be necessary in this regard, before its application in future translational studies.
Although the exact effect of ESWT on the injured tissue is still poorly understood, several mechanisms have been proposed to be involved. Firstly, shockwave therapy promotes the expression of multiple growth factors such as VEGF, brain-derived neurotrophic factor (BDNF), proliferating cell nuclear antigen (PCNA), transforming growth factor beta (TGF-β) and bone morphogenetic protein 2 (Bmp-2) in the affected area. 20 VEGF is a signalling protein with multiple repair roles in the tissue, including the induction of angiogenesis and thus, helping with the normal restoration of blood supply and nutrients. 25 It has also been indicated that it has a neuroprotective effect which reduces apoptosis and axonal degeneration, minimising further damage due to secondary injury. 22 BDNF is another important growth factor which inhibits inflammation and demyelination and suppresses apoptosis as indicated. 20
Secondly, a number of studies have found that the stimulation following ESWT results in improved cell proliferation. This effect was observed on not only endogenous cells, but also exogenous progenitor cells both in vitro and in vivo.26–29 Finally, ESWT has been revealed to improve myelination significantly which then leads to enhancement in axon regeneration, signal transduction and eventually improved neural function. 30 , 31
The current study is subject to several limitations. First, the number of included studies evaluated was relatively small, and second the applied treatment protocols were different. Hence, the effect of several factors, such as energy flux density, frequency, number of impulses and timing of therapy, could not be accurately investigated. For instance, analyses revealed that changes in the number of impulses had a close to significant effect on locomotion, which might be significant if larger sample sizes were used in the studies. Moreover, as only two studies had reported the effect of ESWT on cell survival, publication bias could not be evaluated, and the pertaining results are somewhat unreliable.
The clinical application of ESWT has been growing and the US Food and Drug Administration (FDA) has approved the use of specific shockwave devices on a few conditions, and this relative safety may misguide researchers to move into clinical trials too early. Regarding the heterogeneity between the results of the current meta-analysis, it is strongly suggested for future studies to be directed towards designing more preclinical experiments, focusing on the effect of variables such as energy flux, number of impulses, timing and on the final outcome, before conducting clinical trials. Currently, the human studies on the matter consist of two case reports that have been published in 2019 and 2020, both of which have reported the effects of this modality on neurogenic heterotopic ossification and pain, not on the motor function of the patients. 14 , 32 , 33
Conclusion
The results of the current study indicate that ESWT significantly improves locomotor recovery following SCI through regeneration of the neural tissue. Nonetheless, in spite of promising preclinical results and clinical application of ESWT in various conditions, the current evidence suggests that it may be too soon for designing clinical trials on ESWT in the management of SCI. Further investigations should focus on designing additional preclinical studies, with an effort to reach the safest and the most efficient treatment protocol.
Acknowledgments
None.
Appendix 1: Medline search query via Pubmed
| Search terms |
|---|
| 1. “Ultrasonic Therapy”[mh] OR “Extracorporeal Shockwave Therapy”[mh] OR Ultrasonic Therapy[tiab] OR Extracorporeal Shockwave Therapy[tiab] OR Extracorporeal Shockwave Therapies[tiab] OR Shockwave Therapies, Extracorporeal[tiab] OR Shockwave Therapy, Extracorporeal[tiab] OR Therapy, Extracorporeal Shockwave[tiab] OR Shock Wave Therapy[tiab] OR Shock Wave Therapies[tiab] OR Therapy, Shock Wave[tiab] OR Extracorporeal Shock Wave Therapy[tiab] OR Extracorporeal High-Intensity Focused Ultrasound Therapy[tiab] OR Extracorporeal High Intensity Focused Ultrasound Therapy[tiab] OR HIFU Therapy[tiab] OR HIFU Therapies[tiab] OR Therapy, HIFU[tiab] OR High-Intensity Focused Ultrasound Therapy[tiab] OR High Intensity Focused Ultrasound Therapy[tiab] OR Extracorporeal Spinal Shock Wave[tiab] OR Ultrasonic Therapies[tiab] OR shock wave therapy[tiab] OR shock wave[tiab] OR extracorporeal shock wave therapy[tiab] OR extracorporeal shockwave therapy[tiab] OR shock wave treatment[tiab] OR shockwave therapy[tiab] OR shockwave treatment[tiab] |
| 2. (((((((("spinal"[All Fields] AND "cord"[All Fields] ))) AND (((Contusion) OR injury) OR trauma OR Transection))) OR "Spinal Cord Injuries"[Mesh]))) |
| 3. #1 AND #2 |
Footnotes
Authors’ contributions: Study design: MY.
Data gathering: SNRA, AMN, MY.
Analysis: MY.
Drafting: SNRA.
Revising the paper: All authors.
Availability of data and materials: All data generated or analysed during this study are included in this published article.
Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Consent for publication: Not applicable.
Ethics approval and consent to participate: The study was approved by Iran University of Medical Sciences Ethics Committee. Informed consent was not applicable for the present meta-analysis.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Iran University of Medical Sciences (grant number: 98-4-32-16681).
Role of the sponsor: The Iran University of Medical Sciences had no role in the design and conduct of the study; collection, management, and analysis of the data.
ORCID iDs
Arian Madani Neishaboori https://orcid.org/0000-0002-1920-9299
Mahmoud Yousefifard https://orcid.org/0000-0001-5181-4985
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