Midwest Equine

Feature Article

How shockwave technology and science have evolved

By Jens Stabler, MD

Article Archives LinkShockwave Technology Evolution

Shockwave Technology Evolution

Focused shockwave therapy was first introduced to the equine veterinary market in 1999 by HMT, a Swiss medical company best known for developing the VersaTron. Over the following almost 20 years, the modality has steadily grown to become a standard of care and is available in a majority of lameness practices in North America. In 1999 there were barely 50 devices in the market, today there are almost 1000.

Advances in Technology

Much has changed since 1999. A lot of effort has been put into making shockwave systems more portable and affordable. The very first machines weighed up to 200lbs and cost $80,000 – now they weigh around 30lbs and cost around $30,000. Cables got longer to accommodate usability on large horses and the separate trigger cable was eliminated altogether. Screens have been made brighter and user-friendly interfaces were developed.

However, the key aspect of this technology, the beam, remained the same for a long time. As with all shockwave device manufacturers, HMT's technical background and expertise was rooted in lithotripsy: the use of shockwaves to break kidney stones. The idea to develop devices for orthopedic applications came from this initial treatment protocol and therefore the technology was essentially a derivative and miniaturized version of a lithotripter (Fig. A).

Fig. A

Modern Shockwave and Lithotripter

The technological challenge and objective in lithotripsy is to break up kidney stones and have little or no effect on the surrounding tissue. Consequently, the therapy head's geometry was specifically designed to concentrate the energy in a small focal area and have little effect on the surrounding area.

This basic design carried over into the smaller orthopedic devices, not necessarily because it was the best design but simply because this was the technology available at the time.

In musculoskeletal applications on the other hand, the objective is not to hammer away at a lesion or to "drill a hole in a hole". The actual target zone should always include the area immediately surrounding the lesion. This is where there are viable cells, which can be recruited to aid in the repair. Injury repair generally occurs concentrically. Therefore, the ideal therapy head design for musculo-skeletal applications should be quite different to the old Urology design. In 2013 Switalis, the manufacturer of the NEOvet, launched the first broad beam therapy head followed by an updated version in 2017. By adding more initial power, it was now possible to make the beam much wider and longer for improved penetration, without compromising energy density (Fig. B).

Fig. B

Figure B

Evidence that this design was biologically beneficial was provided in a study performed at the University of Georgia. The results confirmed the hypothesis that the broad beam yields a greater biologic response than the old style narrow beam, even though the latter's energy density is higher. Specifically, this study measured the concentration of extra-cellular growth factor content in PRP exposed to shockwaves as a parameter for platelet activation. The new broad beam design increased PDGF (platelet derived growth factor) by 226% compared to the old style narrow beam design with 133% (Fig. C).

Fig. C

Extracellular PDGF Content

The authors of this study concluded that the data supported the use of ESWT (Extracorporeal Shock Wave Therapy) in combination with PRP for treatment of tendon and ligament injuries in horses.

Advances in Science

In 1999 there was a fair amount of clinical data from human orthopedic medicine supporting the use of shockwave therapy in tendon and ligament injuries. This was followed by several clinical studies validating this new modality for use in horses in the early 2000s, primarily from Colorado State University and Iowa State University. Our understanding of the underlying mechanism of action however was still limited. A review article authored in 2002 by a research group under Professor Wang an orthopedic surgeon summarized the data available at the time regarding the biologic mechanisms of shockwaves in musculo-skeletal applications. Essentially it was shown that exposing tissue to shockwaves (i.e. physical energy) caused the release of various signaling molecules including growth factors and other cytokines (i.e. biologic response), such as BMP (Bone Morphogenetic Protein) eNOS (Extracellular Nitric Oxide Synthase), VEGF (Vaso Endothelial Growth Factor) and PCNA (Proliferating Cell Nuclear Antigen). Downstream, this signaling lead to improved blood supply and tissue regeneration (Fig. D).

Fig. D

Figure D

Until recently, little was known about the upstream signaling events that factored into these biologic responses and about the exact mechanisms involved in tissue regeneration. The rationale for using shockwave therapy (ESWT) in musculo-skeletal conditions such as tendon repair is not only a function of growth factor release and improved blood supply but involves a more complex set of mechanisms and events:

  • Upstream signaling molecules and receptors
  • Immunomodulation
  • Increased tenocyte proliferation and improved tenocyte function
  • Upregulated collagen synthesis
  • Stem cell activation

Shockwave induced ATP-MAPK signaling leads to tissue proliferation

A study published in 2014 addressed the question of the underlying mechanisms by which ESWT increases cell proliferation and promotes wound healing. The illustration shows the cascade of events following ESWT, including:

  • Release of ATP into the extra-cellular space after shockwave exposure
  • Transmission across the cell membrane via P2Y receptor
  • Activation of MAPK/Erk signaling pathway, which has been shown to result in cell proliferation and wound healing

Differential silencing of the various signaling components identified here resulted in the inhibition of the proliferative effects of ESWT (Fig. E).

Fig. E

Differential Silencing - Figure E

Angiogenic response in muscle treated with ESWT mediated by TLR3 receptors

Several studies have shown that shockwave treatment (ESWT) induces new vessel growth and increased blood supply. In 2016 a group of researchers identified Toll-like receptor 3 (TLR3) to mediate the angiogenic response following ESWT noted in earlier studies. TLR3 is a receptor that recognizes RNA and is part of the innate immune system and modulates inflammation through an array of inflammatory cytokines and Type I interferon.

The animal model used here is referred to as the "hind limb ischemia model" and is performed on rats by ligating one of the femoral arteries. ESWT nearly restored limb perfusion in wild type mice after 28 days. This effect was abolished in mice without the gene for TLR3 (TLR3 -/-). ESWT significantly decreased limb necrosis. TLR3 -/- knockout animals did quite poorly, further indicating the significance of TLR3 in the repair and reperfusion process (Fig. F).

Fig. F

Figure F

How do shockwaves affect tendon repair?

ESWT has been used to help heal tendon and ligament injuries for many years. But fairly few specifics about the underlying mechanism of healing were known. The following basic science papers help shed light on the matter.

Immunomodulation – how ESWT affects inflammation

Tendinopathy is known to be mediated by various biochemical pathways involving inflammatory mediators such as MMPs and various cytokines. In this study the authors compared the effects of ESWT on diseased (achilles tendinopathy) compared to healthy human tenocytes.

First, they demonstrated a significant elevation of several inflammatory markers Matrix Metallo Proteinases (MMP) and Interleukins (IL) in diseased vs. healthy tenocytes without exposure to ESWT. MMP1, 2 and 13 as well as IL6 were significantly increased in diseased cells (Fig. G).

Fig. G

Figure G

Next, they exposed healthy tenocytes to ESWT. The expression of MMPs remained unchanged. Among the tested Interleukins only IL1 showed a slight increase vs the untreated control. IL6 and IL13 remained the same. In diseased tenocytes on the other hand, ESWT caused a significant reduction of the pathologic expression of MMP1 and MMP13 as well as IL6 (Fig. H).

Fig. H

Figure H

MMPs play a crucial role in degrading collagen matrix and there is a significant reduction of pro-inflammatory IL6. Both findings provide evidence that ESWT has beneficial immunomodulatory effects and support the use of ESWT in tendinopathy especially even in the early stages after injury.

Increased cell proliferation and improved function

Another study using primary cultured tenocytes as their base model demonstrated significant increase in tenocyte proliferation and collagen synthesis in cells exposed to shockwaves compared to negative controls. These findings correlate with the clinical observation using ultrasound that tendon injuries tend to "fill in" quicker.

Another interesting observation here is that ESWT reduced phenotypic drift. In culture, classically elongated fibroblast-like cells turn into increasingly heterogenous ovoid tenoblast cells. In other words, ESWT inhibits the de-differentiation or stabilizes cultured tenocytes. The clinical relevance may be that healthy, classically elongated tenocytes are active producers of Type I collagen which possesses tensile strength – whereas injured cells produce Type III collagen and have lower secretive activity.

Similar observations were made in another study using non-cultured, diseased and healthy tenocytes obtained from patients undergoing achilles tendon surgery. Proliferation rate of tenocytes is significantly increased in both groups, but even more so in diseased cells (Fig. I).

Fig. I

Figure I

The authors also ran functional protocols, such as the scratch test, demonstrating improved functionality of treated tenocytes versus control (see below). This test measures the migratory response of treated tenocytes in diseased vs healthy cells with or without ESWT. The gap closure was much more rapid and complete in cells treated with ESWT (Fig. J).

Fig. J

Figure J

ESWT accelerates muscle regeneration

Treatment of sore backs with shockwave therapy is meanwhile a standard of care in many practices. Certainly, the induction of increased blood supply significantly contributes to the clinical response but it is not the only mechanism of action. Data from rats and human cell cultures indicate that ESWT upregulates the proliferation rates of mesenchymal stem cells, smooth and cardiac muscle cells as well as tenocytes as discussed above. This raises the question whether ESWT affects muscle repair in similar ways, specifically by influencing the muscle's main population of reserve cells, so called satellite cells which are essentially local progenitor cells.

The regenerative capacity of skeletal muscle depends mainly on satellite cells. In response to muscle damage these quiescent precursor cells become activated, proliferate and differentiate into new muscle fiber. An experiment was conducted to investigate the effects of a single ESWT session on satellite cell recruitment and growth of regenerating muscle fibers in an animal model with cardiotoxin induced muscle damage. As hypothesized, the results clearly demonstrated that ESWT accelerates the time to regeneration in rat skeletal muscle corresponding with significantly greater satellite cell activation (Fig. K: see greater immunofluorescence in treatment group below).

Fig. K

Figure K

These are just a few of the studies and facts we cover as part of each and every installation. It is our belief that know-how is key to the successful use of any tool including shockwave systems. We encourage discerning and critical choices when it comes to the use of shockwave therapy in clinical practice. Understanding the basic science behind the method of action of ESWT is essential.

Fig. L

Figure L