Therapeutic ultrasound has been used in a variety of medical applications such as lithotripsy and dentistry for several decades. Ultrasound in the frequency range from 20 to 45 kHz is often used in medical applications due to its unique feature of selective disruption of inelastic rigid materials. Since the 1960s, there have been several studies exploring the use of therapeutic ultrasound for vascular intervention. In 1965, Anschuetz and Bernard conducted an in vitro study on the effect of therapeutic ultrasound on atherosclerotic arteries and suggested its use for atherosclerotic plaque ablation.1 That same year, Lane and Minot demonstrated that ultrasonic energy could defragment calcified plaque in cadaveric coronary arteries.2 This work was the beginning of 4 decades of studies and development of therapeutic ultrasound for vascular interventions.

In 1974, Sobbe et al conducted the first published animal study using a wire transmission member to deliver ultrasonic energy to the lesion for vascular plaque disruption.3 Starting in the 1980s, several studies focused on the development of a catheter prototype for initial clinical testing. In 1989, Siegel et al performed the first clinical study on patients with peripheral vascular disease using percutaneous catheter-delivered ultrasound for arterial recanalization.4 The results from the initial pilot clinical study were very positive, with three of four chronic total occlusions (CTOs) recanalized and no evidence of arterial emboli, dissection, spasm, or perforation. A number of clinical studies were conducted in the 1990s and demonstrated promising results for CTO recanalization using catheter-delivered therapeutic ultrasound.5-9

In 1991, Demer et al performed an in vitro study on atherosclerotic cadaver arteries and found that the arterial distensibility was increased after 2 minutes of exposure to a therapeutic ultrasound catheter.6 In 2001, Gunn et al published the results of a clinical study on 40 patients with single-vessel stenosed (not occluded) coronary arteries using catheter-delivered therapeutic ultrasound and standard percutaneous transluminal coronary angioplasty (PTCA) treatment. The results showed a 40% lower mean lesion yield pressure in the PTCA treatment in the group with ultrasound, suggesting improved distensibililty in atherosclerotic plaque with therapeutic ultrasound treatment. 10

THE CROSSER® RECANALIZATION SYSTEM

Despite the initial success of using therapeutic ultrasound in arterial lesions and CTOs, the lack of trackability, large catheter profile, and insufficient CTO crossing efficacy limited the applicability of this technology. In the early 2000s, the Crosser® Recanalization System was developed by FlowCardia, Inc. to improve on the first-generation ultrasound device performance and provide a low-profile system with good trackability and an increased CTO recanalization success rate. The device was first evaluated in the coronary arteries. In the FACTOR (FlowCardia’s Approach to Chronic Total Occlusion Recanalization) clinical study, the Crosser® System demonstrated a 60.8% crossing success rate in 125 patients with coronary CTOs.11 With this early success, the device was further modified for use in the peripheral arteries. In the PATRIOT (Peripheral Approach to Recanalization in Occluded Totals) clinical trial, the Crosser® System was used to treat 85 patients with CTOs in peripheral arteries.12 It successfully crossed 84% of guidewire-resistant CTOs with an average ultrasonic energy activation time of 126 seconds. The Crosser® System received CE Mark in the EU in 2004 and was cleared by the FDA in 2007 for CTO crossing.

The Crosser® System consists of a generator, transducer, foot switch, and catheter, and is used in conjunction with the Flowmate® Injector System, which provides saline irrigation (Figures 1 and 2). The Crosser® System was designed to facilitate crossing of CTOs using catheter-delivered ultrasonic vibrational energy at a frequency of 20 kHz.

The Crosser® Catheter is connected to the generator through a handheld transducer. The Crosser® Generator converts AC power into high-frequency electrical current, which then excites the piezoelectric crystals within the transducer, causing them to expand and contract. The piezoelectric crystals convert high-frequency current from the Crosser® Generator into ultrasonic energy. This energy is amplified, and the ultrasonic wave is propagated down the catheter via a core wire to the tip. Upon activation, the Crosser® Catheter tip advances approximately 20 μm with each stroke, initiating mechanical impact with the CTO material. In addition, saline is injected through the Crosser® Catheter via the Flowmate® Injector and exits through the small irrigation lumens in the catheter tip for cooling and cavitation.

The peripheral Crosser® Catheter portfolio includes rapid-exchange (RX) and over-the-wire (OTW) systems, along with a lower-profile system that does not use a guidewire for delivery. Each Crosser® Catheter includes a hub with irrigation port, hydrophilic-coated outer body over a transmission wire, irrigation outlets, and metal tip. The Crosser® Catheter 14S and 14P have a 1.1-mm tip and are compatible with 0.014-inch guidewires utilized for both above- and below-the-knee CTO crossing applications. The Crosser® Catheter S6 is a smaller-profile system that is not delivered over a guidewire with a 0.6-mm tip used in highly calcified lesions above and below the knee. The small tip focuses vibrational energy providing twice the efficiency of the Crosser® Catheter 14S, as shown in a bench occlusion model.13† Compared to first-generation ultrasonic CTO crossing devices, the Crosser® Catheters offer small catheter profile and improved trackability in the peripheral anatomy and are considered major improvements over the early catheter designs.

MECHANISM OF CROSSER® SYSTEM RECANALIZATION

The CTO crossing mechanism of the Crosser® Catheter is a combination of mechanical vibration and cavitation. Mechanical fragmentation is caused by the high-frequency vibration of the Crosser® Catheter tip impacting the calcified plaque. As shown in the high-speed video snapshots in Figure 3, the tip of the Crosser® Catheter vibrates a distance of approximately 20 μm at 20,000 cycles per second. This type of low-amplitude and high-frequency mechanical vibration enables the catheter tip to act like a vibrational “jackhammer” and ablate the calcified plaque into particles that are carried away by the bloodstream.

Cavitation is a key component of CTO recanalization using the Crosser® System. High-frequency vibration of the Crosser® Catheter creates strong negative and positive pressure cycles in the surrounding fluid. Cavitation bubbles are formed from the dissolved gas on the negative side of the pressure cycle when the catheter tip is retracting.14,15 The bubbles quickly collapse on the positive side of the pressure cycle (Figure 3). The collapse of cavitation bubbles generates strong mechanical shock waves that erode the calcified plaque. In addition, microstreaming occurs as a secondary effect caused by the collapse of cavitation bubbles. When cavitation bubbles collapse, a jet-like ejection occurs, resulting in high-velocity fluid streaming, which also helps ablate the calcified lesion.16 Cavitation-induced shock waves and microstreaming together create a localized region with intense shear stresses and break the internal fibrin structure of calcified plaque for mechanical penetration. Figure 4 shows the microscopic pictures of a Class 4 super-hard plaster stone (Bego USA) before and after Crosser® Catheter activation.13 The tip of the Crosser® Catheter was placed close but not in physical contact with the stone surface during activation. The strong erosion on the stone surface after activation demonstrates the effect of cavitation and microstreaming of the Crosser® Catheter.†

BIOEFFECT OF THERAPEUTIC ULTRASOUND-BASED CTO RECANALIZATION

The most distinctive feature of therapeutic ultrasound-based CTO recanalization is plaque ablation selectivity. Specifically, tissues with high collagen and elastin content are extremely resistant to ultrasonic disruption; however, tissues lacking these components can be very susceptible to disruption.5,15 In 1965, Anschuetz and Bernard concluded that normal and atherosclerotic arterial tissue were more resistant to damage than other tissue types. Other early researchers observed that ultrasound destroys atherosclerotic plaque but leaves the adjacent vascular wall relatively unaffected.1,18 Ernst investigated this theory further to determine whether high-intensity ultrasound could discriminate between fibrous or calcified plaque and normal arterial wall. The results of the study showed that ultrasonic disruption is inversely related to tissue elasticity—the time to perforate cadaveric arterial wall sites was significantly longer than the fibrous or calcified plaque sites.18

As an illustration, the bench demonstration in Figure 5 further shows the plaque ablation selectivity of the Crosser® Catheter. In this bench demonstration, the Crosser® Catheter successfully drills through a guidewire-resistant stone but does not penetrate a thin elastic membrane layer of latex after crossing. The demonstration shows the effectiveness of the Crosser® Catheter on inelastic materials and also indicates that the elastic materials can absorb the impact of the ultrasonic vibration from the tip of the Crosser® Catheter.†

In addition to tissue ablation selectivity, researchers have also investigated the potential risk of peripheral embolization due to ultrasonic ablation of calcific lesions related to the size of resultant particles. Many of the studies on other therapeutic ultrasound devices show that more than 90% of debris particles after ultrasonic ablation are < 20 µm in size.5,8,18 Microscopic analysis also reveals that a majority of them are cholesterol monohydrate crystals.5 The small size of the resultant debris potentially reduces the risk of peripheral embolization when using therapeutic ultrasound for CTO recanalization. In a clinical study using a catheter-delivered therapeutic ultrasound device for coronary arterial obstruction, no evidence of arterial emboli, heart block, arterial perforation, dissection, or vasospasm was observed.8

In the previously discussed FACTOR (coronary) and PATRIOT (peripheral) clinical trials with the Crosser® Catheter, adverse events were tracked 30 days postprocedure, and rates were consistent with other published data on similar devices. In both trials, no Crosser® Catheter-related clinical perforations were found.12

SUMMARY

Therapeutic ultrasound for CTO recanalization has evolved from the 1965 in vitro study to today’s standard clinical use status. Clinical studies in the past 50 years have demonstrated that this technique provides an effective treatment solution for plaque ablation. The use of therapeutic ultrasound by the Crosser® System provides the device tissue ablation selectivity and differentiates it from other competitive CTO devices. As ultrasound technology continues to evolve, physicians will be able to treat more patients with CTOs, and its use may broaden to other medical applications.

All authors are employees of Bard Peripheral Vascular, Inc. in Tempe, Arizona. Angela Crall may be reached at angela.crall@crbard.com.

†Data on file. Bench test results may not necessarily be indicative of clinical performance. Different tests may yield different results.

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  13. Data on file at Bard. (G62123).
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