Feasibility, effectiveness, and safety of a novel cryo-balloon targeted lung denervation technique in an animal model

Abstract

Background and objective

Targeted lung denervation (TLD) is a pulmonary interventional procedure for COPD that aims to disrupt parasympathetic nerve input to the lung to reduce the clinical consequences of cholinergic hyperactivity. TLD has been proven to be a safe procedure and effectively alleviate symptoms and reduce the onset of exacerbation. In the present study, we developed a novel cryo-balloon TLD system and evaluated its feasibility, safety, and effectiveness.

Methods

A preclinical study was performed on twelve sheep, four were tested for airway resistance alterations before and after TLD, two were tested for the Hering-Breuer reflex (HBR) and the remaining six sheep were evaluated for 28 days to assess the safety and effectiveness of the procedure.

Results

After an observation period of 28 days, significant disruption of vagal innervation to the lung could be validated by both histological and physiological assessments. The operation time was shorter than traditional procedure, with minimal adjacent tissue injury and no device-related adverse events.

Conclusions

The novel cryo-balloon TLD procedure was feasible, safe, and effective. In comparison with the traditional procedure, this treatment system required shorter operation time and caused less denervation-induced damage to adjacent tissues.

Introduction

Chronic obstructive pulmonary disease (COPD) is a clinical syndrome characterised by chronic respiratory symptoms, abnormal lung structure, and pulmonary dysfunction [6] and is the third leading cause of death globally [16]. Despite substantial advancements in COPD management, many patients experience major symptoms and frequent exacerbations even after optimal pharmacological treatment [7,13]. The vagus nerves running within the airway play an important role in COPD progression by mediating broncho-contraction, mucus hypersecretion, and airway inflammation [1,12]. Thus, anticholinergic therapy targeting the vagus nerve system may reduce the incidence of exacerbations [4,16,22,23]. Targeted lung denervation (TLD), a novel interventional technique, has been used to permanently disrupt neuronal acetylcholine release and has proven its safety and therapeutic potential in a series of clinical trials [[18], [19], [20]]. Recently, Valipour et al. reported that TLD may be an effective complement to routine muscarinic receptor blockade therapy for COPD by significantly reducing respiratory-related adverse events and the onset of exacerbations that require hospitalisation [17].

Cryoablation is a widely used interventional approach in which the tissue is subjected to cooling, freezing, and thawing processes, thereby causing irreversible damage or even necrosis of the target tissues. In comparison with radiofrequency ablation, cryoablation induces less local inflammation, and scar formation within airway [21]. Cryoablation may also effectively inhibit the growth of granulation tissue and exert minimal effects on the adjacent normal mucosa and cartilage thus has been used to alleviate airway stenosis caused by thermal ablation [15]. As for denervation surgery, cryoablation has been used in treating refractory hypertension by disrupting renal artery sympathetic nerves [11,14]. Therefore, we developed a novel cryo-balloon that can be placed at the main bronchus through a bronchoscopic operating channel to perform TLD.

In this report, we presented a series of preclinical studies on sheep demonstrating the physiologic and histopathologic evidence for the use of the cryo-balloon TLD with desired feasibility and safety profile. In comparison with the traditional procedure, this technique required shorter operation time and caused less denervation-induced damage to adjacent tissues. To our knowledge, this was the first attempt to apply cryo-balloon in TLD surgery, and this technique may significantly reduce the operation time while ensuring safety and effectiveness.