Lower extremity peripheral artery disease (PAD) affects over 200 million people worldwide, with symptoms ranging from asymptomatic presentations to critical limb ischemia (1). As the global population ages, the prevalence of PAD has surpassed 8.5 million cases in developed countries (2). Clinical manifestations may include varying degrees of lower limb pain, claudication, and ischemia-induced weakness. The 2024 American College of Cardiology/American Heart Association guidelines recommend tailored rehabilitation exercises and lipid-lowering drugs to alleviate lower limb discomfort and delay disease progression (3). However, in advanced PAD, endovascular revascularization often becomes the only option to prevent limb amputation. Although advancements in endovascular treatment (EVT) devices have mitigated challenges such as thrombosis and chronic total occlusion, severe calcification within the tunica media of peripheral arteries remains a major unresolved obstacle.

Calcified plaques are challenging to remove from lesions but can be redistributed along the arterial wall through balloon compression, improving arterial compliance and facilitating subsequent drug-coated balloon (DCB) or stent-graft implantation for revascularization. However, balloon overexpansion to compress hard calcified plaques increases the risk of arterial rupture. Current calcium modification techniques face two critical limitations: (i) Directional atherectomy removes calcified plaques by crushing and extracting them from the artery, but meta-analyses indicate that it may increase the risk of arterial rupture by 38% [relative risk: 1.38, 95% confidence interval (CI): 1.12–1.71] (4), and (ii) excimer laser ablation (ELA) is another method used to treat arterial calcification, which can generate ultraviolet light at a wavelength of 308 nm to disrupt soft lipid plaques and is commonly used to treat in-stent restenosis. However, insufficient clinical evidence in PAD patients limits the evaluation of its safety (5). Notably, both methods require direct contact with calcified lesions, making it difficult to address calcifications within the arterial tunica media. This limitation remains a critical challenge of EVT in patients with PAD.

To address this challenge, an effective and innovative endovascular device was developed to fracture calcified plaques without direct contact. Intravascular lithotripsy (IVL), adapted from ultrasound lithotripsy technology used in the urinary system, was first applied to treat calcified plaques in coronary arteries, achieving a procedural success rate of 98.0% in heavily calcified lesions (6, 7). The density difference between calcified plaques and normal blood vessels creates an impedance mismatch in their acoustic properties. As a result, tissues with higher density, such as calcified plaques, experience greater pressure from non-aggregated low-intensity shockwaves. The IVL device generates unfocused circumferential pulses through the electrohydraulic effect, enabling the disruption of calcified lesions without direct contact with the plaques (8).

Prospective clinical trials of IVL have demonstrated its potential to enhance the efficacy of EVT for calcified lesions (9–11). However, the efficiency of IVL in disrupting plaques with varying calcification characteristics and its potential impact on normal vascular walls remain a concern. To address these limitations, this study introduces a novel intravascular shockwave lithotripsy system (LiqMagic P18, Sonosemi Medical) specifically engineered to target tunica media calcifications. Through in vitro calcification models and in vivo validation in porcine models, the device demonstrated high efficacy and safety across heterogeneous calcification subtypes. Our experiments quantitatively demonstrated the disruption efficiency of the IVL device on different characteristic calcifications and the degree of damage to normal blood arteries. Thus, an IVL device may offer a reliable therapeutic option for treating severely calcified lesions of the tunica media.

This study provides a comprehensive evaluation of a novel IVL system by integrating an in vitro gypsum model and in vivo animal experiments. In this study, using models with different thicknesses and eccentric calcifications, the IVL device demonstrated favorable therapeutic effects on calcifications with varying characteristics. By testing different oversized ratios, the optimal IVL balloon oversize ratio was identified using an in vitro gypsum model. In the in vivo study, DSA imaging showed that the IVL device provided better immediate lumen acquisition and a lower follow-up lumen loss rate compared to PTA balloons. These findings suggest that IVL may offer superior immediate postoperative and short-term therapeutic effects for patients with PAD. The in vitro study also demonstrated that the IVL device achieved good lumen acquisition without compromising the integrity of endothelial and vascular smooth muscle cells, indicating good biosafety. Overall, the study quantitatively demonstrated the calcification-disrupting efficacy of IVL on different types of calcifications and highlighted its potential to improve clinical outcomes for patients with PAD.

As calcification increases, the risk of vascular complications after treatment (18, 19). Calcification within the tunica media has long posed a challenge in EVT for patients with PAD, as few devices can effectively remove or disrupt calcified plaques embedded deep within the vessel wall (8). Traditional treatments often involve increasing balloon pressure to crack calcification in the tunica media, which may be partially effective but carries a risk of vascular rupture when excessive dilation is applied (20, 21). Although directional atherectomy can more thoroughly address arterial calcification and may be the only EVT method capable of physically removing plaques, a high rate of arterial rupture and other postoperative complications related to the device pose a challenge to its clinical safety (4). Compared with other lesion preparation devices such as atherectomy (4) and ELA (5), IVL offers distinct advantages, particularly for heavily calcified lesions and those located in the tunica media. This makes IVL a valuable addition to the range of lesion preparation tools for PAD, addressing a critical need for treating complex calcified lesions, especially those within the tunica media where direct-contact devices may be less effective or pose higher risks (22).

Intravascular lithotripsy is a novel technique for modifying calcified plaques, utilizing a single-use balloon catheter embedded with lithotripsy emitters. It adopts concepts similar to those of shockwave lithotripsy used for nephrolithiasis, generating pulsatile sonic pressure waves to safely disrupt calcification. The device was first described in the treatment of peripheral arteries in 2016 (23), and gained European and United States Food and Drug Administration approvals in 2018 (24).

Early reports showed that the use of IVL has a consistent reduction in stenoses and low procedural complication rates in the PAD treatment (9, 25). In the recent study, Stefano Fazzini et al. (26). reported the mid-term outcomes of shockwave intravascular lithotripsy in the calcified illiac arteries. The mid-term results of the retrospective cohort study showed that IVL has a high surgical success rate and clinical technical success rate with a low incidence of device adverse events and complications, and has high target artery patency during the 24-month follow-up period. A systematic review and meta-analysis study revealed that the application of IVL can reduce the stenosis of the target artery by 59.31% (95% CI: 53.30%–65.31%), and only 1.25% (95% CI: 0.60%–2.61%) D-grade or above flow restriction dissection can be found after the IVL treatment (24). A prospective clinical study reported that the application of IVL can improve the ankle brachial index (ABI) from 0.74 ± 0.20 to 0.97 ± 0.18 at 30 days (27), and Radaideh et al. (28) reported that the ABI can be increased from 0.7 ± 0.1 to 0.9 ± 0.2 at six months, and the PAD II clinical study revealed the ABI was increased from 0.7 ± 0.2 to 1.0 ± 0.2 at 12 months (11). Clinical cohort study also indicated that the use of IVL can reduce the Rutherford classification from R3 to R0 in PAD patients within a 6 and 12 follow-up period (11). A short-term retrospective study revealed that there were low target lesion revascularisation (TLR) rates within a 12-month follow-up period (11, 28). Furthermore, meta-analysis results also revealed the use of additional stents was only 15.89% (95% CI: 5.22%–39.34%) after IVL treatment (24). These results demonstrated that IVL has good effectiveness and satisfactory safety in reducing the degree of calcified arterial stenosis and improving the treatment efficacy of EVT in severe PAD patients.

Compared with other IVL devices, our IVL device has some characteristics. Firstly, our IVL device has five symmetrically distributed unfocused electrohydraulic emitters. This design generates 360° homogeneous shockwaves (1.0–9.7 MPa) that have deep penetration (up to 2.5 mm) to reach tunica media-embedded calcifications. Furthermore, our IVL has lower operating pressure (4 atm vs. 10 atm in PTA balloons and 6 atm in the shockwave IVL device) minimizes mechanical stress on the vessel wall to avoid barotrauma to the normal tissue (11). These advantages will provide more effective and safe selection of luminal preparation equipment for patients with severe calcified PAD, although the exact clinical efficacy requires further prospective, large-scale, long-term follow-up head-to-head clinical confirmation.

IVL leverages the difference in density between calcified plaques and normal blood vessels, which creates an impedance mismatch in acoustic properties. As a result, tissues with higher density experience greater pressure from non-aggregated low-intensity shockwaves, enabling calcification disruption without direct contact. Although prospective clinical studies (10, 29) have shown that IVL can promote the efficacy of EVT in PAD patients with moderate to severe calcified, the disrupting efficacy of IVL on different characteristic calcifications has not been quantitatively demonstrated. Through this study, we quantitatively described the therapeutic efficacy of IVL on different characteristics of calcified lesions for the first time through an in vitro experiment based on a customer-modified gypsum calcification model, revealing the quantitative description of IVL's disruption efficacy on different characteristics of calcified lesions. Our research could provide basic data support for personalized IVL device design for PAD patients.

The previous studies (17) have shown that IVL can alleviate static barotrauma to the treated artery by reducing the working balloon's maximum working pressure. In the present study, our in vitro quantitative experiments showed that an over-expansion (target lesion diameter: IVL working balloon diameter) ratio of 1.04:1 was sufficient to provide IVL to disrupt calcified plaques, and excessively increasing the working pressure of the IVL working balloon does not bring additional plaque disruption benefits. This will provide clinical interventional physicians with reference data.

It is worth noting that prospective clinical studies have shown that IVL can improve therapeutic efficacy by promoting the degree of eccentric calcification disruption in coronary arteries (30, 31), indicating that IVL has a good therapeutic effect on eccentric calcification. Similarly, previous studies have shown that eccentric calcification was associated with postoperative re-intervention in peripheral arteries (32). Our in vitro quantitative study showed that IVL has a good disruption effect on eccentric calcification, indicating the potential role of IVL in improving the therapeutic efficacy of EVT for peripheral arterial disease with eccentric calcification. However, its exact efficacy still needs to be supported by real-world prospective clinical data. It is worth noting that our gypsum model experiments revealed that IVL efficacy plateaued for calcifications ≥3.0 mm, even with double-frequency treatment, whereas 2.5 mm plaques showed significant improvement. This nonlinear response stems from thickness-dependent energy attenuation. For 2.5 mm calcifications, initial pulses generate microfractures that reduce acoustic impedance; subsequent pulses exploit these defects through stress concentration and cyclic fatigue. In contrast, thicker plaques (≥3.0 mm) dissipate shockwave energy before critical stress thresholds are reached, limiting incremental benefit. This aligns with urological lithotripsy models where successive pulses enhance stone fragmentation (16). These findings highlight the importance of personalized IVL dosing based on calcification morphology—a strategy warranting clinical validation.

In the in vivo study, IVL significantly improved immediate lumen acquisition and reduced late lumen loss, leading to better luminal outcomes compared to PTA balloons. Histopathological and immunofluorescence staining analyses showed that IVL did not increase endothelial damage or vascular smooth muscle loss compared to PTA balloons, indicating that IVL has good biosafety, which was similar to the previous IVL animal study (15). Furthermore, the histopathological scoring results showed that the use of IVL did not affect the structure of normal blood vessel walls, and did not lead to more severe negative vascular remodeling after usage. These results indicated that IVL did not affect the structure of normal blood vessel walls, which was consistent with the previous study (15). In our in vivo study, the lumen diameter expansion measurements were interpreted strictly as the mechanical compliance response of the healthy artery to the IVL or PTA balloon inflation procedure itself. We measured the immediate increase in lumen diameter relative to the pre-treatment baseline within the treated segment. This assesses the device's ability to achieve acute luminal gain in a compliant vessel, which is a fundamental step before application in calcified, non-compliant vessels. While it does not directly measure “calcification disruption” efficacy (which was the focus of the in vitro gypsum model), it provides crucial data on the acute lumen acquisition and potential barotrauma compared to standard PTA. Thus, from our perspective, the current preclinical experiments provide quantitative research data on the immediate acquisition and damage of non-calcified normal swine blood vessels by the IVL device, which will provide a necessary preliminary research basis for the exact effectiveness and safety of IVL in aortic calcification swine models in the future.

While our healthy swine model allowed controlled assessment of IVL's safety profile, we acknowledge it does not fully replicate the complex calcified milieu of human PAD. The absence of medial calcification limits direct extrapolation of efficacy outcomes to diseased human arteries. Future studies using large-animal models with induced medial calcification were warranted to validate therapeutic efficacy in pathophysiological contexts.

This study has several limitations. Firstly, the current preclinical study was based on a small healthy swine animal cohort, which was designed to conform to the 3R principles of experimental animals (33), including Replacement, Reduction, and Refinement, to obtain the most valuable results with the smallest sacrifice of animals. Although experiments in healthy animals have shown that IVL obtains better lumens than PTA, the exact efficacy of IVL in a large animal arterial calcification model with a larger cohort and longer follow-up period needs further exploration. Furthermore, expanding the animal sample size is essential to better assess the actual impact of IVL devices on lumen acquisition. The present study also lacks comparison with other established devices (e.g., shockwave IVL) and other debulking devices, which would be addressed through a head-to-head comparison study in a future study. On the other hand, long-term follow-up experiments based on a large animal arterial calcification model are needed to evaluate the long-term effectiveness and safety of IVL on calcified blood arteries. Also, the current research lacked an accurate evaluation of the effectiveness and safety of this IVL device in real-world PAD patients, as well as a comparison with other debulking devices. It is necessary to perform multicenter, prospective, long-term follow-up clinical trials based on clinical PAD patients to accurately evaluate the effectiveness and safety of current IVL devices for patients with severe calcified lesions, even compared with other debulking devices in a head-to-head comparison study. And this limitation would be addressed in our further study.

Despite these limitations, this multifaceted study provides robust evidence supporting the efficacy and safety of this novel IVL system for treating calcified PAD lesions. The findings from in vitro and in vivo investigations collectively suggest that this IVL device holds significant potential for improving outcomes in patients with PAD and challenging calcified lesions. Future studies should focus on long-term clinical outcomes, larger patient cohorts, and the development of more physiologically relevant animal models of arterial calcification to further validate these findings and explore the full potential of this IVL technology.

In conclusion, the IVL device has demonstrated effectiveness and safety as a lumen preparation tool for target artery revascularization.