Ann Thorac Surg 1998;66:1772-1776
© 1998 The Society of Thoracic Surgeons
Original articles: general thoracic
Comparison of tissue reactions in the tracheal mucosa surrounding a bioabsorbable and silicone airway stents
Antti Korpela, MDa,
Pertti Aarnio, MDa,
Hannu Sariola, MDa,
Pertti Törmälä, PhDa,
Ari Harjula, MDa
a Department of Thoracic and Cardiovascular Surgery, Helsinki University Central Hospital, Helsinki, Finland
Accepted for publication May 10, 1998.
Address reprint requests to Dr Korpela, Department of Surgery, Päijät-Häme Central Hospital, Keskussairaalankatu 7, 15850 Lahti, Finland
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Abstract
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Background. Treatment of tracheobronchial stenosis is problematic. Conservative methods include stenting the stenotic area, but an ideal stent has not yet been developed. Bioabsorbable airway stents offer benefits; the extraction of the device is unnecessary, and the airway preserves its normal function after stent resorption. The aim of this study was to examine the suitability of self-reinforced poly-L-lactide as a material for an airway stent.
Methods. A spiral airway stent made of 0.7-mm wire of self-reinforced poly-L-lactide was implanted operatively in 9 rabbits intratracheally; silicone stents served as controls.
Results. Silicone stents had a tendency to become stenosed with encrustation material and to develop a hyperplastic polyp at both ends. Self-reinforced poly-L-lactide stents were well tolerated and caused no foreign body reaction, and they had a tendency to penetrate into the tracheal wall. They had disappeared at the end of the follow-up of 10 months.
Conclusions. This experimental study showed that bioabsorbable self-reinforced poly-L-lactide is a promising material for an airway stent for treatment of airway stenosis.
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Introduction
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Tracheobronchial stenoses can be caused by tracheobronchomalacia, extrinsic compression, postintubation tracheal injuries, sequelae after tracheostomy, or malign or benign tumors. They may develop also after surgical operations. After the introduction of cyclosporine, lung transplantations became an option for end-stage lung disease. Since then the anastomotic healing of the airways has remained problematic. At the present time, overall incidence of lethal airway complications in lung transplantation is estimated to be 2% to 3%, and that of late stricture, 7% to 14%. The risk of lethal airway complications seems currently to be similar for both isolated lung or heart–lung transplantation; the incidence of nonlethal complications appears to be higher after isolated lung grafting [1].
Fibrous and some tumoral stenoses can be treated with resection and end-to-end anastomosis. Short diaphragm-like stenoses and granulomas can be handled with endoluminal therapy, such as endoluminal resection or dilation, cryotherapy, or laser therapy. Intrabronchial stenting is the best choice for long fibrous stenoses and for nonresectable tumors. The silicone T-tube for stenting the airway after repair of stenosis in the low subglottic region was initially developed and described by Montgomery in 1965 [2]. Endoscopic intubation of malignant tumors of the tracheobronchial tree with a Souttar tube without tracheostomy was introduced by Clarke in 1980 [3]. Since then, different types of intratracheal and intrabronchial stents made of silicone [4, 5] or other materials have been used as a treatment for tracheobronchial stenosis. Self-expanding metallic stents were the next step in the development of intraluminal airway stents [6–8], and they offered certain benefits compared with silicone stents.
Compared with other tracheobronchial stents available, a bioabsorbable bronchial stent offers theoretical benefits. Its extraction is unnecessary, and the organ preserves its normal function after absorption of the device. Bioabsorbable materials are metabolized to water and carbon dioxide by hydroxylation inside normal tissue. Bioabsorption time can be modified by the choice of the basic molecule of the polymer and by manufacturing methods. Biocombatibility properties have been shown to be relatively good in organs other than the airways [9, 10]. Bioabsorbable pins and screws made of polyglycolide, for example, are already in clinical use in orthopedic surgery.
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Material and methods
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Poly-L-lactide was our choice of material for the stent because, of the basic molecules available, it has the longest biodegradation time. The molecular weight of the poly-L-lactide stent was 660,000, and its material was reinforced to increase its strength and retention in vivo. These self-reinforced (SR) PLLA spiral stents were made of 0.7-mm wire with an outer diameter of 5.5 mm and a length of 12 mm (Fig 1). Silicone, the longest used and most common material for tracheobronchial stents, was chosen as a control material. The silicone stents were tubes 1 mm thick with 5- or 6-mm outer diameter and a length of 12 mm.
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Fig 1. The mechanical construction of the bronchial stent made of biodegradable self-reinforced poly-L-lactide was a helical spiral made of 0.7-mm wire with an outer diameter of 5.5 mm.
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Test animals were allocated to two groups. Group A with silicone stents comprised 9 rabbits with a mean weight of 3.3 kg (range, 2.5 to 40. kg). Group B with self-reinforced poly-L-lactide stents comprised 9 rabbits, mean weight 3.3 kg (range, 2.1 to 4.0 kg). The rabbits were anesthetized with 0.75 mg atropine, 20 mg ketamine, 300 µg medetomide, and 1.0 mg/kg body weight diazepam. Procaine penicillin (150,000 IU) was the prophylactic antibiotic. All these drugs were administered subcutaneously. The animals maintained spontaneous breathing without intubation. In the midline the cervical trachea was prepared under direct visualization for implantation of the stent, with unnecessary dissection avoided to not interfere with blood circulation of the trachea. The trachea was opened transversely between cartilage rings for two-thirds of its circumference. The stent was implanted intratracheally and fixed with the same continuous 5-0 polypropylene suture used to close the tracheotomy. Bronchoscopic examinations were not done because of the difficulties encountered with rabbit oropharyngeal anatomy. After the mean follow-up of 14 (15, 16, 12), 24 (24, 24, 24), and 36 (33, 38, 38) weeks in group A with silicone stents and 12.7 (12, 12, 14), 24 (24, 24, 24), and 40 (40, 40, 40) weeks in group B with SR-PLLA stents, the animals were killed with an overdose of sodium pentobarbital.
The cervical trachea was excised and divided longitudinally into two pieces, one fixed in 4% formalin solution for histologic examinations and the other in 2% buffered glutaraldehyde solution for scanning electron microscopic studies. Histologic examinations were made of longitudinal sections of the whole stented area. From paraffin-embedded tissue material, 4-µm-thick sections were cut and stained with hematoxylin and eosin. The magnitude of inflammatory changes, fibrosis, and epithelial changes were assessed semiquantitatively using a four-stage grading system as follows: 0 = normal, 1 = mild changes, 2 = moderate changes, and 3 = severe changes. The tissue samples for scanning electron microscopic studies were dehydrated in ethanol and critical point dried (Balzers CPD 020, Balzers Union Ltd, Liechtenstein), mounted on aluminum studs, and coated with gold by means of a Jeol JFC-1100 sputtering device (Jeol Ltd., Tokyo, Japan). A Jeol JSEM-820 scanning electron microscope at 5 kV acceleration voltage, at the Electron Microscopy Unit of the Institute of Biotechnology, University of Helsinki, was used in scanning electron microscopic studies. Changes in the epithelial cell layer and ciliated cells were evaluated. Because of the nature of findings in histologic and scanning electron microscopic studies, quantitative analysis was not performed.
All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). The study protocol was approved by the institutional committee for test animal research.
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Results
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All animals tolerated the surgical operation and the implantation of the stent well. No infection or other complications that would have indicated earlier killing of the animals developed during the follow-up. In group A with silicone stents, 2 animals (6- and 9-month follow-up) had stridor from excitement at the time of killing. In the macroscopic dissection the bronchial wound had healed well in all animals, with no stenosis developing at the bronchotomy site. After a follow-up time of 6 and 9 months, light brown obstructive material was visible inside the stent. Mucosal hyperplasia at both ends of the stents had also developed.
In group B with SR-PLLA stents 2 animals (3- and 6-month follow-up) also had excitement-induced stridor when killed. In all these animals the bronchial lumen was fully open. After 10 months’ follow-up, all these stents had disappeared except for a short part of the spiral that was fixed with nonabsorbable suture to the bronchial wall. In 3 animals (follow-up 6, 6, and 3 months) the stents had compressed at the same level as the surrounding bronchial mucosa. The remaining stents were detached when the specimens and the spirals were cut for fixation. Grooves that the stents had compressed in the bronchial wall were visible. All the stents in rabbits killed at 6 months after implantation had lost some of their mechanical strength.
Histologic examination of group A with silicone stents showed ulceration of the epithelium under the stent. At the ends of the stent, reserve cell hyperplasia had developed forming a hyperplastic polyp (Fig 2). At the same area in the submucosa there was moderate chronic lymphocytic inflammation and moderate eosinophilia. In group B with SR-PLLA stents, the spirals of the stent had compressed the tissue causing an ulceration of the epithelium, and between these ulcerations there was reserve cell hyperplasia. In this same area there was mild to moderate eosinophilia and chronic lymphosytic inflammation. The foreign-body reaction was minimal in both groups. In the silicone group there were slightly more histologic changes such as eosinophilia and chronic lymphosytic inflammation, but no significant differences existed between the groups. To summarize, both types of stents were well tolerated, except that silicone stents had a tendency to be occluded by encrustation material.
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Fig 2. Tracheal epithelium 6 months after implantation showing ulceration of the epithelium under the silicone stent and reserve cell hyperplasia forming a hyperplastic polyp at the end of the stent (arrow). (Hematoxylin and eosin; x40 before 46% reduction.)
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In the SEM studies, group B with SR-PLLA stents showed an intact epithelial cell layer with ciliated and nonciliated cells 3 months postoperatively (Fig 3) and with a uniform carpet of ciliated cells between the spirals of the stent at the end of the follow-up (Fig 4) comparable with normal tracheal epithelium in rabbits. In group A with silicone stents the epithelium had disappeared in some areas, showing only uncovered basal membrane and cell debris (Fig 5); part of the surface was covered with flat cells with or without microvilli and with solitary ciliated cells. The assessment was similar for group B, regarding areas lying under spirals of the stent.
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Fig 3. Scanning electron micrograph showing intact epithelial cell layer formed of nonciliated (short arrow) and ciliated cells (long arrow) in a rabbit with self-reinforced poly-L-lactide stent, 3 months after operation. (x3,600 before 26% reduction.)
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Fig 4. Scanning electron micrograph of the trachea in a rabbit with self-reinforced poly-L-lactide stent, 10 months after operation, shows a continuous carpet of ciliated cells comparable with normal rabbit tracheal epithelial cell layer. (x4,400 before 35% reduction.)
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Fig 5. Scanning electron micrograph of a specimen of a rabbit with silicone stent 4 months after operation, showing uncovered basal membrane and some red blood cells (arrow). (x3,600 before 33% reduction.)
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Comment
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Bronchial stenosis after lung transplantation is a specific problem, often because of scar stenosis at the anastomotic level with or without previous anastomotic dehiscence. Except for endobronchial laser or cryotherapy, which are useful for some short stenoses and granulomas, these are best handled by insertion of a silicone or metallic stent [7]. The advent of lung transplantation has increased the number of potential candidates for the use of tracheobronchial stents, because airway anastomosis still constitutes a surgical weak point [11]. A rate of 7% to 14% of bronchial complications is reported, mainly from dehiscence, stenosis, or malacia of the anastomosis in most series [1, 12, 13]. In their series of 57 patients treated with a silicone stent, Sonett and colleagues [5] concluded that endoscopic stenting provides effective palliation of tracheobronchial stenoses both with benign and with malignant causes. They considered such stenting the primary management option for airway obstruction after lung transplantation [5].
Previously, stents made of silicone were used in most series after the introduction of the Montgomery T-tube in 1965 [2]. Although silicone stents are widely used, they have certain disadvantages. Because they are relatively thick, the internal diameter of the stent is thus smaller than the normal airway lumen. They interfere with normal airway mucociliary function, which can result in accumulation of secretions inside the stent and obstruction of its lumen. Silicone stents are difficult to place in the right main bronchus without obstructing the orifice of the upper lobe. After insertion they also have a tendency to migrate [14]. On the other hand, silicone stents are usually well tolerated and can be readjusted after insertion if necessary.
Metallic expandable wire stents have a low internal-to-external diameter ratio. They cannot usually migrate after insertion, and the mucociliary clearance function is better maintained [15]. The usefulness of the expandable metallic stent was reported in 1986 by Wallace and associates [8], whose stent was constructed of 0.018-inch-thick stainless steel wire formed in a cylindrical zigzag configuration of 5 to 10 bends. These stents were first implanted into the trachea and bronchi of 11 dogs. This stent, called the Gianturco stent, was then used to treat 2 patients with bronchial stenosis and bronchomalacia after tracheobronchial reconstruction. In 1990, Varela and coinvestigators [16] successfully treated 5 patients with tracheobronchial disease with the Gianturco stent. None had complications secondary to stent placement, and their clinical problems resolved satisfactorily, although the longest follow-up time was only 12 months. Complications associated with Gianturco stents, however, have been reported [6, 17]. The Schneider Wallstent, developed for endovascular use, also has been used for treating airway stenosis [6, 7], and several other types of stents for intratracheal and intrabronchial use have also been developed. All types have their limitations, and the ideal stent for use in the tracheobronchial tree has not yet been developed.
Because stenting of the tracheobronchial stenosis after lung transplantation can be only temporary [5], bioabsorbable stents are optimal. In our study we tested tolerance and tissue reactions of a bioabsorbable stent made of self-reinforced poly-L-lactide within the normal airway, compared with those caused by a stent made of silicone. The construction of this bioabsorbable stent is rigid enough to maintain the airway lumen during the active scarring process. Thereafter the lumen should remain open, and from our previous study, the epithelium and ciliated cells restores to a normal airway epithelium. The construction of the stent can be modified, but this type of stent, which does not totally cover the wall of the airway, cannot be recommended for the treatment of endoluminal tumors. These absorbable stents were very well tolerated and caused only minor tissue reactions. Scanning electron microscopic studies showed the ciliated cell layer was well spared between the spirals of the stent. The stents had disappeared within the 10-month follow-up.
Silicone and metallic stents used in the tracheobronchial tree for the treatment of airway stenosis both have disadvantages; the ideal stent has not yet been developed. Because the need for stenting the airways can be only temporary, particularly in benign and posttransplantation stenosis, a bioabsorbable stent can serve as an alternative means for treating airway stenosis. In this study, an airway stent made of self-reinforced poly-L-lactide showed biocombatibility good enough to make it a promising material for an airway stent. This absorbable stent and its construction require further investigation before clinical applications begin.
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References
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Abstract
Introduction
