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Various preclinical studies of the developed Eustachian tube (ET) stent are currently underway, but it has not yet been used in clinical practice. In preclinical studies, ET scaffolds have been limited to scaffold-induced tissue proliferation. The efficacy of the cobalt-chromium sirolimus-eluting stent (SES) in inhibiting stent-induced tissue proliferation after stent placement was studied in a porcine ET model. The six pigs were divided into two groups (ie control group and SES group) with three pigs in each group. The control group received an uncoated cobalt-chromium stent (n = 6), and the SES group received a cobalt-chromium stent with a sirolimus-eluting coating (n = 6). All groups were sacrificed 4 weeks after stent placement. Stent placement was successful in all ETs without complications associated with surgery. None of the stents could retain their original round shape, and mucus accumulation was observed in and around the stents in both groups. Histological analysis showed that the area of tissue proliferation and the thickness of submucosal fibrosis in the SES group were significantly lower than in the control group. SES appears to be effective in inhibiting scaffold-induced tissue proliferation in ET pigs. However, further studies are needed to confirm the optimal materials for stents and antiproliferative drugs.
The Eustachian tube (ET) has important functions in the middle ear (eg, ventilation, preventing the transfer of pathogens and secretions to the nasopharynx)1. Also includes protection against nasopharyngeal sounds and regurgitation2. The ET is usually closed, but opens with swallowing, yawning, or chewing. However, ET dysfunction can occur if the tube does not open or close properly3,4. Dilated (obstructive) dysfunction of ET depresses ET function and, if these functions are not preserved, may develop into acute or chronic otitis media, one of the most common diseases in ENT practice. Current treatments for ET dysfunction (eg, nasal surgery, ventilation tube placement, and medication) are used in patients. However, these treatments have limited efficacy and may lead to ET obstruction, infection, and irreversible tympanic membrane perforation3,6,7. Eustachian tube balloon angioplasty has been introduced as an alternative treatment for dilated ET 8 dysfunction. Although several studies since 2010 have shown that Eustachian tube balloon repair is superior to conventional treatment for ET dysfunction, some patients do not respond to dilatation8,9,10,11. Thus, stenting may be an effective treatment option12,13. Despite numerous ongoing preclinical studies evaluating the technical feasibility and tissue response after stent placement in ET, stent-induced tissue hyperplasia due to mechanical damage remains a significant postoperative complication 14,15,16,17,18,19. drug-coated, loaded with anti-proliferative agents improve this situation.
Drug-eluting stents have been used to inhibit in-stent restenosis caused by tissue and neointimal hyperplasia after stent placement. Typically, stent scaffolds or linings are coated with drugs (eg, everolimus, paclitaxel, and sirolimus)20,23,24. Sirolimus is a typical antiproliferative drug that inhibits several steps of the restenosis cascade (eg, inflammation, neointimal hyperplasia, and collagen synthesis)25. Therefore, this study hypothesized that sirolimus-coated stents could prevent stent-induced tissue hyperplasia in ET pigs (Figure 1). The aim of this study was to investigate the efficacy of sirolimus-eluting stents (SES) in inhibiting stent-induced tissue proliferation after stent placement in a porcine ET model.
Schematic illustration of a cobalt-chromium sirolimus-eluting stent (SES) for the treatment of Eustachian tube dysfunction, showing that the sirolimus-eluting stent inhibits stent-induced tissue proliferation.
Cobalt-chromium (Co-Cr) alloy stents were fabricated by laser cutting Co-Cr alloy tubes (Genoss Co., Ltd., Suwon, Korea). The stent platform uses an open double bond with a unified architecture for high flexibility with optimal radial force, shortening and compliance. The stent had a diameter of 3 mm, a length of 18 mm, and a strut thickness of 78 µm (Fig. 2a). The dimensions of the Co-Cr alloy frame were determined based on our previous study.
Cobalt-chromium (Co-Cr) alloy stent and metal guide sheath for Eustachian tube stent placement. The photographs show (a) a Co-Cr alloy stent and (b) a stent-clamped balloon catheter. (c) The balloon catheter and stent are fully deployed. (d) A metal guide sheath was developed for the porcine Eustachian tube model.
Sirolimus was applied to the surface of the stent using ultrasonic spray technology. SES is designed to release almost 70% of the original drug load (1.15 µg/mm2) within the first 30 days after placement. An ultra-thin 3 µm coating is applied only to the proximal side of the stent to achieve the desired drug release profile and minimize the amount of polymer; this biodegradable coating contains a copolymer of lactic and glycolic acids and a proprietary blend of poly(1)-lactic acid)26,27. Co-Cr alloy stents were crimped onto balloon catheters 3 mm in diameter and 28 mm long (Genoss Co., Ltd.; Fig. 2b). These stents are available in South Korea for the treatment of coronary heart disease.
The newly developed metal guide shell for the pig ET model was made of stainless steel (Fig. 2c). The inner and outer diameters of the shell are 2 mm and 2.5 mm, respectively, the total length is 250 mm. The distal 30 mm sheath was bent into a J-shape at a 15° angle to the axis to allow easy access from the nose to the nasopharyngeal orifice of the ET in the pig model.
This study was approved by the Institutional Animal Care and Use Committee of the Asan Institute of Life Sciences (Seoul, South Korea) and complies with the National Institutes of Health Guidelines for the Humane Treatment of Laboratory Animals (IACUC-2020-12-189). . The study was conducted in accordance with ARRIVE guidelines. This study used 12 ETs in 6 pigs weighing 33.8-36.4 kg at 3 months of age. The six pigs were divided into two groups (ie control group and SES group) with three pigs in each group. The control group received an uncoated Co-Cr alloy stent, while the SES group received a Co-Cr alloy stent eluting sirolimus. All pigs had free access to water and feed and were kept at 24°C ± 2°C for a 12-hour day-night cycle. Subsequently, all pigs were sacrificed 4 weeks after stent placement.
All pigs received a mixture of 50mg/kg zolazepam, 50mg/kg teletamide (Zoletil 50; Virbac, Carros, France) and 10mg/kg xylazine (Rompun; Bayer HealthCare, Les Varkouzins, Germany). then the tracheal tube was placed by inhalation of 0.5-2% isoflurane (Ifran®; Hana Pharm. Co., Seoul, Korea) and oxygen 1:1 (510 ml/kg/min) for anesthesia. Pigs were placed in the supine position and baseline endoscopy (VISERA 4K UHD rhinolaryngoscope; Olympus, Tokyo, Japan) was performed to examine the nasopharyngeal orifice of ET. A metal guide sheath was advanced through the nostril to the nasopharyngeal orifice of ET under endoscopic control (Fig. 3a, b). A balloon catheter, a corrugated stent, is inserted through the introducer into the ET until its tip meets resistance in the osteochondral isthmus of the ET (Fig. 3c). The balloon catheter was fully inflated with saline to 9 atmospheres, as determined by the manometer monitor (Fig. 3d). The balloon catheter was removed after stent placement (Fig. 3f), and the nasopharyngeal opening was carefully evaluated endoscopy for surgical complications (Fig. 3f). All pigs underwent endoscopy before and immediately after stenting, as well as 4 weeks after stenting, to assess the patency of the stent site and surrounding secretions.
Technical steps for placing a stent in the eustachian tube (ET) of a pig under endoscopic control. (a) Endoscopic image showing the nasopharyngeal opening (arrow) and inserted metal guide sheath (arrow). (b) Insertion of a metal sheath (arrow) into the nasopharyngeal opening. (c) A stent-clamped balloon catheter (arrow) is introduced into the ET through a sheath (arrow). (d) The balloon catheter (arrow) is fully inflated. (e) The proximal end of the stent protrudes from the ET orifice of the nasopharynx. (f) Endoscopic image showing stent lumen patency.
All pigs were euthanized by administering 75 mg/kg potassium chloride by ear vein injection. Median sagittal sections of the porcine head were performed using a chainsaw followed by careful extraction of ET scaffold tissue samples for histological examination (Supplementary Fig. 1a,b). ET tissue samples were fixed in 10% neutral buffered formalin for 24 hours.
ET tissue samples were sequentially dehydrated with alcohol of various concentrations. Samples were placed in resin blocks by infiltration with ethylene glycol methacrylate (Technovit 7200® VLC; Heraus Kulzer GMBH, Wertheim, Germany). Axial sections were performed on embedded ET tissue specimens in the proximal and distal sections (Supplementary Fig. 1c). The polymer blocks were then mounted on acrylic glass slides. Resin block slides were microground and polished with silicon carbide paper of various thicknesses up to a thickness of 20 µm using a grid system (Apparatebau GMBH, Hamburg, Germany). All slides were subjected to histological evaluation with hematoxylin and eosin staining.
Histological evaluation was performed to assess the percentage of tissue proliferation, the thickness of the submucosal fibrosis, and the degree of inflammatory cell infiltration. The percentage of tissue hyperplasia with a narrow ET cross-sectional area was calculated by solving the equation:
The thickness of the submucosal fibrosis was measured vertically from the stent struts to the submucosa. The degree of inflammatory cell infiltration was subjectively judged by the distribution and density of inflammatory cells, namely: 1st degree (mild) – a single single leukocyte infiltration; 2nd degree (mild to moderate) – focal leukocyte infiltration; 3rd degree (moderate) – combined. with leukocytes unable to distinguish between individual loci; grade 4 (moderate to severe) leukocytes diffusely infiltrating the entire submucosa, and grade 5 (severe) diffuse infiltration with multiple foci of necrosis. The thickness of the submucosal fibrosis and the degree of inflammatory cell infiltration were obtained by averaging eight points around the circumference. Histological analysis of ET was performed using a microscope (BX51; Olympus, Tokyo, Japan). The measurements were obtained using the CaseViewer software (CaseViewer; 3D HISTECH Ltd., Budapest, Hungary). The analysis of histological data was based on the consensus of three observers who did not take part in the study.
The Mann-Whitney U-test was used to analyze differences between groups as needed. A p < 0.05 was considered statistically significant. A p < 0.05 was considered statistically significant. Значение p < 0,05 считалось статистически значимым. A p value < 0.05 was considered statistically significant. p < 0.05 被认为具有统计学意义。 p < 0.05 p < 0,05 считали статистически значимым. p < 0.05 was considered statistically significant. A Bonferroni-corrected Mann–Whitney U-test was performed for p values < 0.05 to detect group differences (p < 0.008 as statistically significant). A Bonferroni-corrected Mann–Whitney U-test was performed for p values < 0.05 to detect group differences (p < 0.008 as statistically significant). U-критерий Манна-Уитни с поправкой на Бонферрони был выполнен для значений p <0,05 для выявления групповых различий (p <0,008 как статистически значимое). Bonferroni-adjusted Mann-Whitney U test was performed for p values <0.05 to detect group differences (p<0.008 as statistically significant).对p 值< 0.05 进行Bonferroni 校正的Mann-Whitney U 检验以检测组差异（p < 0.008 具有统计学意义）。对p 值< 0.05 进行Bonferroni 校正的Mann-Whitney U U-критерий Манна-Уитни с поправкой на Бонферрони был выполнен для значений p < 0,05 для выявления групповых различий (p < 0,008 был статистически значимым). Bonferroni-adjusted Mann-Whitney U-test was performed for p < 0.05 to detect group differences (p < 0.008 was statistically significant). Statistical analysis was performed using SPSS software (version 27.0; SPSS, IBM, Chicago, IL, USA).
All porcine stent placements were technically successful. A metal guide sheath was successfully placed in the nasopharyngeal orifice of ET under endoscopic control, although mucosal injury with contact bleeding was observed in 4 of 12 specimens (33.3%) during metal sheath insertion. After 4 weeks, palpable bleeding spontaneously stopped. All pigs survived to the end of the study without stent-related complications.
Endoscopy results are shown in Figure 4. During the 4-week follow-up, the stents remained in place in all pigs. Mucus accumulation in and around the ET stent was observed in all (100%) ETs in the control group and three (50%) of the six ETs in the SES group, and there was no difference in incidence between the two groups (p = 0.182). None of the installed stents could maintain a round shape.
Endoscopic images of the Eustachian tube (ET) of a pig in the control group and the group with a cobalt-chromium stent (CXS) eluting sirolimus. (a) Baseline endoscopic image taken before stent placement showing the nasopharyngeal opening (arrow) of ET. (b) Endoscopic image taken immediately after stent placement showing ET of stent placement. Contact bleeding has been observed due to the metal guide sheath (arrow). (c) Endoscopic image taken 4 weeks after stent placement shows mucus accumulation around the stent (arrow). (d) Endoscopic image showing that the stent cannot remain round (arrow).
Histological findings are shown in Figure 5 and Supplementary Figure 2. Tissue proliferation and submucosal fibrous proliferation between the stent posts in the ET lumen of both groups. The mean percentage of tissue hyperplasia area was significantly larger in the control group than in the SES group (79.48% ± 6.82% vs. 48.36% ± 10.06%, p < 0.001). The mean percentage of tissue hyperplasia area was significantly larger in the control group than in the SES group (79.48% ± 6.82% vs. 48.36% ± 10.06%, p < 0.001). Средний процент площади гиперплазии тканей был значительно больше в контрольной группе, чем в группе СЭС (79,48% ± 6,82% против 48,36% ± 10,06%, p < 0,001). The mean area percentage of tissue hyperplasia was significantly greater in the control group than in the SES group (79.48% ± 6.82% vs. 48.36% ± 10.06%, p < 0.001). SES 组（79.48% ± 6.82% vs. 48.36% ± 10.06%，p < 0.001）。 48.36% ± 10.06%，p < 0.001）。 Средний процент площади гиперплазии тканей в контрольной группе был значительно выше, чем в группе СЭС (79,48% ± 6,82% против 48,36% ± 10,06%, p < 0,001). The mean area percentage of tissue hyperplasia in the control group was significantly higher than in the SES group (79.48% ± 6.82% vs. 48.36% ± 10.06%, p < 0.001). Moreover, the mean thickness of submucosal fibrosis was also significantly higher in the control group than in the SES group (1.41 ± 0.25 vs. 0.56 ± 0.20 mm, p < 0.001). Moreover, the mean thickness of submucosal fibrosis was also significantly higher in the control group than in the SES group (1.41 ± 0.25 vs. 0.56 ± 0.20 mm, p < 0.001). Более того, средняя толщина подслизистого фиброза также была значительно выше в контрольной группе, чем в группе СЭС (1,41 ± 0,25 против 0,56 ± 0,20 мм, p < 0,001). Moreover, the mean thickness of submucosal fibrosis was also significantly higher in the control group than in the SES group (1.41 ± 0.25 vs. 0.56 ± 0.20 mm, p < 0.001). SES 组（1.41 ± 0.25 vs. 0.56 ± 0.20 mm，p < 0.001）。 0.56±0.20mm，p<0.001）。 Кроме того, средняя толщина подслизистого фиброза в контрольной группе также была значительно выше, чем в группе СЭС (1,41 ± 0,25 против 0,56 ± 0,20 мм, p < 0,001). In addition, the mean thickness of submucosal fibrosis in the control group was also significantly higher than in the SES group (1.41 ± 0.25 vs. 0.56 ± 0.20 mm, p < 0.001). However, there was no significant difference in the degree of inflammatory cell infiltration between the two groups (control group [3.50 ± 0.55] vs. SES group [3.00 ± 0.89], p = 0.270).
Analysis of the histological examination of two groups of stents placed in the Eustachian lumen. (a, b) The area of tissue hyperplasia (1 of a and b) and the thickness of submucosal fibrosis (2 of a and b; double arrows) were significantly greater in the control group than in the SES group with strut stenting (black dots), area of narrowed lumen (yellow) and original stent area (red). The degree of inflammatory cell infiltration (3 of a and b; arrows) did not differ significantly between the two groups. (c) Histological results of percent area of tissue hyperplasia, (d) thickness of submucosal fibrosis, and (e) degree of inflammatory cell infiltration 4 weeks after stent placement in both groups. SES, cobalt-chromium sirolimus eluting stent.
Drug-eluting stents help improve stent patency and prevent stent restenosis20,21,22,23,24. Stent-induced strictures result from granulation tissue formation and fibrous tissue changes in various non-vascular organs, including the esophagus, trachea, gastroduodenum, and bile ducts. Drugs such as dexamethasone, paclitaxel, gemcitabine, EW-7197, and sirolimus are applied to the surface of the wire mesh or stent coating to prevent or treat tissue hyperplasia after stent placement29,30,34,35,36. Recent innovations in the field of multifunctional stents using fusion technology are being actively investigated for the treatment of non-vascular occlusive diseases37,38,39. In a previous study in a porcine ET model, scaffold-induced tissue proliferation was observed. Although stent development in ET is not well understood, tissue response after stent placement has been found to resemble that of other nonvascular luminal organs19. In the present study, SES was used to inhibit scaffold-induced tissue proliferation in a porcine ET model. Sirolimus is toxic to pancreatic islets and beta cell lines, reduces cell viability and enhances apoptosis40,41. This effect may help to inhibit the formation of tissue proliferation by stimulating cell death. Our study showed that the first use of drug-eluting stents in ET effectively inhibited stent-induced tissue proliferation in ET.
The balloon-expandable Co-Cr alloy stent used in this study is readily available as it is commonly used to treat coronary artery disease 42 . In addition, Co-Cr alloys have mechanical properties (for example, high radial strength and inelastic forces) 43 . According to the endoscopy of the current study, the Co-Cr alloy stent used for ET of pigs cannot maintain a round shape in all pigs due to insufficient elasticity and does not have the ability to self-expand. The shape of the inserted stent can also be changed by movement around the ET of a living animal (eg, chewing and swallowing). The mechanical properties of Co-Cr alloy stents have become a disadvantage in the placement of porcine ET stents. In addition, placement of a stent in the isthmus may result in permanently open ET. Persistent open or extended ET allows speech and nasopharyngeal sounds, gastrointestinal reflux, and pathogens1 to travel up into the middle ear, causing mucosal irritation and infection. Therefore, permanent nasopharyngeal openings should be avoided. Therefore, given the structure of ET cartilage, scaffolds are preferably made from shape memory alloys with superelastic properties, such as nitinol. In general, heavy discharge was found in and around the nasopharyngeal orifice of the stent. Since the normal mucociliary movement of mucus is blocked, the secret is expected to accumulate in scaffolds protruding from the nasopharyngeal opening. Prevention of ascending middle ear infection is one of the main objectives of ET, and placement of stents that protrude beyond ET should be avoided, since direct contact of stents with nasopharyngeal bacterial flora can lead to increased ascending infections.
Eustachian tube balloon plasty through the nasopharyngeal opening is a new minimally invasive treatment for ET dysfunction aimed at opening and widening the cartilaginous portion of ET8,9,10,46. However, the underlying therapeutic mechanism has not been identified47 and its long-term outcomes may be suboptimal8,9,11,46. Under these conditions, temporary metal stenting may be an effective treatment option for patients who do not respond to Eustachian tube balloon repair, and the feasibility of ET stenting has been demonstrated in numerous preclinical studies. Poly-l-lactide scaffolds were implanted through the tympanic membrane in chinchillas and rabbits to assess tolerability and degradation in vivo17,18. In addition, a sheep model was created to evaluate the profile of metal balloon expandable stents in vivo. In our previous study, a porcine ET model was developed to investigate the technical feasibility and evaluation of stent-induced complications,19 providing a solid basis for this study to investigate the efficacy of SES using previously established methods. In this study, SES was successfully localized to the cartilage and effectively inhibited tissue proliferation. There were no stent-related complications, but there was mucosal injury caused by the metal guide sheath with contact bleeding that resolved spontaneously within 4 weeks. Given the potential complications of metal sheaths, improving the SES delivery system is urgent and critical.
This study has some limitations. Although histological findings varied significantly between groups, the number of animals in this study was too small for a reliable statistical analysis. Although three observers were blinded to assess inter-observer variability, the degree of submucosal inflammatory cell infiltration was determined subjectively based on the distribution and density of inflammatory cells due to the difficulty of enumerating inflammatory cells. Since our study was conducted using a limited number of large animals, a single dose of the drug was used, in vivo pharmacokinetic studies were not conducted. Further studies are needed to confirm the optimal dosage of the drug and the safety of sirolimus in ET. Finally, the 4-week follow-up period is also a limitation of the study, so studies on the long-term effectiveness of SES are needed.
The results of this study demonstrate that SES can effectively inhibit mechanical injury-induced tissue proliferation after placement of balloon-expandable Co-Cr alloy scaffolds in a porcine ET model. Four weeks after stent placement, variables associated with stent-induced tissue proliferation (including area of tissue proliferation and thickness of submucosal fibrosis) were significantly lower in the SES group than in the control group. SES appears to be effective in inhibiting scaffold-induced tissue proliferation in ET pigs. Although further research is needed to test the optimal stent materials and dosages of drug candidates, SES has local therapeutic potential in preventing ET tissue hyperplasia after stent placement.
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