Feasibility, effectiveness, and safety of a novel cryo-balloon targeted lung denervation technique in an animal model
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.
Section snippets
Study design
Twelve sheep (6 male, 6 female) underwent cryo-balloon denervation. All procedures were under the approval of Shanghai General Hospital Institutional Review Board (Permit Number: 2018KY201) (Shanghai, China) and conducted following the protocols of Shanghai Committee for the Accreditation of Laboratory Animal. All operations were performed under optimal anaesthesia with every effort made to minimise sheep suffering. Four sheep were tested for airway resistance alterations before and after TLD;
Feasibility of the cryo-balloon TLD procedure
When denervation process began, during which the balloon was rapidly filled with nitrogen and the surface temperature rapidly dropped to −160 °C. The overall operation time for unilateral bronchus in vivo was 15 s, and the subsequent thawing process required approximately 1 min. After completion of bilateral cryoablation, direct inspection of the airway was performed under bronchoscopy.
Only mild discoloration and minimal bleeding were seen acutely immediately after cryoablation (Fig. 1C). The
Discussion
The vagus nerve is the tenth cranial nerve that originates from the medulla, runs in the carotid sheath through the neck into the chest, and reaches the parasympathetic ganglia in the visceral organs. The vagus nerve system regulates airway smooth muscle tone, mucus secretion, and local inflammation, thus playing an important role in various pulmonary diseases including COPD [5,24]. Modulation of vagus nerve function through pharmacologic blockade of muscarinic receptors can effectively improve
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgments
Qiang Li would like to acknowledge the support from National Key R&D Program (2018YFC1313700) and the “Gaoyuan” project of Pudong Health and Family Planning Commission (PWYgy2018-06). Part of the study was funded by NINGBO SENSCURE BIOTECHNOLOGY CO. LTD.
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These authors contributed equally to the paper.