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Objectives/hypothesis: The ideal trachea replacement would be a living graft that is genetically identical to the host, avoiding the need for immunosuppression. We have developed a mouse model of syngeneic tracheal transplant that results in long-term survival without graft stenosis or delayed healing. To understand how host cells contribute to tracheal transplant integration, we quantified the populations of host cells in the graft and native trachea following implant., Study Design: Tracheal transplant, tracheal replacement, regenerative medicine, animal model., Methods: Tracheal grafts were obtained from female C57BL/6 mice and orthotopically transplanted into syngeneic male recipients. Cohorts were euthanized on day 14, day 45, and day 90 post-transplantation. Host and graft tracheas were explanted and analyzed by histology. Male host cells were quantified using fluorescence in situ hybridization, and macrophages were quantified with immunofluorescence., Results: Evidence of host-derived cells was found in the midgraft at the earliest time point (14 days). Host-derived cells transiently increased in the graft on day 45 and were predominantly found in the submucosa. By day 90, the population of host-derived cells population declined to a similar level on day 14. Macrophage infiltration of host and graft tissue was observed at all time points and was greatest on day 90., Conclusions: Tracheal graft integration occurs by way of subacute transient host-cell infiltration and is primarily inflammatory in nature. Host-cell contribution to the graft epithelium is limited. These data indicate that creation of living, nonimmunogenic tracheal graft could serve as a viable solution for long-segment tracheal defects., Level of Evidence: 3 Laryngoscope, 131:E340-E345, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: In this study, pirfenidone's role about reducing tracheal stenosis by suppressing fibrosis and inflammation was examined., Methods: Tracheotomy was performed on 14 rats, and their cannulas were fixed to tracheotomy area by stoma suture. Two working groups were established. Rats in the first group were given 15 mg/kg/day (1 mL pirfenidone solution) pirfenidone intraperitoneally for 10 days. In the second group as a control group, 1 mL saline solution was applied intraperitoneally. Ten days later, rats were decanulated and kept alive for 3 more weeks. Anesthetized rats were sacrificed on day 30. All rat tracheas were resected between the first and seventh rings. Epithelial damage, inflammation, and fibrosis were determined histopathologically; diameters of intratracheal lumen and their mucosal thickness parameters were determined histomorphometrically; and TGFβ-1 (the growth factor beta), TNFα (tumor necrosis factor alpha), and IL-1β (Interleukin-1 beta) values were determined immunohistochemically., Results: According to the parameters of the control group, fibrosis; diameters of intratracheal lumen; and values of TGFβ-1, TNFα, and IL-1β were found to be statistically significant., Conclusion: In our study, it was found that pirfenidone reduces fibrosis and narrowing of intratracheal lumen diameter significantly., Level of Evidence: NA Laryngoscope, 129:E178-E186, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: This study was conducted to determine whether a nitinol stent coated with doxycycline prevents tracheal inflammation and fibrosis in a rabbit., Methods: A nitinol stent coated with doxycycline was designed by us. Twelve rabbits were divided into three groups: normal, control (nondoxycycline-coated stent), and doxycycline-coated stent group. The stents were inserted into the tracheal lumen through the oral cavity. Tracheal granulation was evaluated and graded by laryngoscopy. Histological examinations evaluated the inflammatory response and fibrosis. Real-time polymerase chain reaction (PCR) and Western blot assessed the changes to the extracellular matrix (ECM)., Results: Endoscopic findings showed that the nitinol stent coated with doxycycline resulted in lesser granulation tissue in the trachea than the noncoated stent. Histologic examination further revealed that the doxycycline-coated stent was associated with decreased inflammatory cells and reduced fibrosis, compared to the noncoated stent. In PCR and Western blot, the doxycycline-coated stent showed lower expression of ECM components inducing fibrosis., Conclusion: A nitinol stent coated with doxycycline showed favorable effects in reducing tracheal inflammation and fibrosis in a rabbit model. Further research is required to study the beneficial effects of local application of doxycycline for prevention of tracheal stenosis., Level of Evidence: NA. Laryngoscope, 128:1558-1563, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: Acquired laryngotracheal stenosis is a challenging problem for otolaryngologists. Several studies suggest tacrolimus may inhibit post-transplant airway stenosis that occurs with coronary drug-eluting stents. The objective of the present study was to determine whether tacrolimus modulates wound healing of the airway mucosa and prevents laryngotracheal stenosis in an acute injury animal model., Study Design: Basic science., Methods: The laryngotracheal mucosa of rats was scraped with a nylon brush through the tracheostoma. Tacrolimus (0.2 mg/kg or 1.0 mg/kg) was systemically administered intramuscularly for 5 days. Nine days after scraping, the pathological changes and the degree of stenosis were assessed by hematoxylin and eosin staining or by immunohistochemical staining for nuclear factor of activated T cell and interleukin 2., Results: Lumen stenosis resulted from hyperplasia of the airway epithelium and a thickened submucosal layer with extensive fibrosis, angiogenesis, and collagen deposition. There was a significant preventive effect on airway stenosis at the tracheal and cricoid levels in the low-dose (0.2 mg/kg) tacrolimus-treated animals, compared to the untreated animals (P < .05). This effect was insignificant with treatment by high-dose tacrolimus (1.0 mg/kg). Immunohistochemistry showed that, after tacrolimus treatment, the expressions of nuclear factor of activated T cell and interleukin 2 were downregulated in submucosal fibroblasts, neovascular cells, and glandular cells., Conclusions: This study suggests that low-dose systemic tacrolimus has a preventive effect on laryngotracheal stenosis by inhibiting the activation of immune cells in the injured airway mucosa via the calcineurin/nuclear factor of activated T cell/interleukin 2 pathway., Level of Evidence: NA., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: This study was conducted to determine whether a surface-modified tracheal T-tube can prevent tracheal stenosis in a rabbit model., Study Design: Animal model study., Methods: We designed surface-modified tracheal T-tubes in which silicone rubber was modified by coating it with hyaluronic acid (HA) or polyethylene glycol (PEG). Sixteen rabbits were divided into four insertion groups: normal, silicone tube, silicone tube coated with HA, and silicone tube coated with PEG. Surface-modified tubes were inserted into the tracheal lumen after a scraping injury on the inner tracheal mucosa around the preformed tracheostoma. Laryngoscopy was performed to evaluate formation of stenosis in the trachea. Histological examinations were performed to evaluate epithelial thickness, inflammatory response, and fibrosis., Results: Endoscopic finding showed that the HA- and PEG-coated tube groups had less granulation tissue in the trachea than the noncoated tube group. Greater epithelialization was observed in the noncoated tube group than in the normal group. HA- and PEG-coated tube groups showed a tendency to decreasing epithelialization compared with the noncoated tube group. More inflammatory cells were observed in the noncoated tube group than in the normal group, and fewer inflammatory cells were observed in the HA- and PEG-coated tube groups than in the noncoated tube group. The noncoated tube group showed a greater area of fibrosis than the HA- and PEG-coated tube groups., Conclusions: A surface-modified tracheal T-tube may have a favorable effect on reducing tracheal stenosis in a rabbit model. We suggest that local application of HA and PEG should be further researched for prevention of tracheal stenosis. Our rabbit model could be helpful in providing an additional scenario for evaluating new strategies to prevent tracheal stenosis., Level of Evidence: NA, (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To compare the tracheal changes after applying a new open dilatational tracheostomy (ODT) technique with those from a conventional open tracheostomy (COT) with vertical cartilage incision in a growing animal model., Study Design: Prospective, experimental investigation in a rabbit model., Materials and Methods: Thirteen New Zealand white rabbits as a pediatric model were divided into three groups: six rabbits had COT (n = 6), another six underwent an ODT (n = 6), and one rabbit acted as a control. Each rabbit underwent tracheostomy by assigned procedures on the first day. On day 8, they were decannulated. On day 15, their tracheas were harvested. We examined the gross findings and histologic changes of each tracheal segment at the stomal level. In addition, we analyzed three parameters: the quotient of the stomal and nonstomal segment in sagittal diameter, coronal diameter, and cross-sectional area., Results: The framework of cartilages at the stomal level were more distorted in the COT group. Histologic examination also showed buckling of the anterior tracheal wall, loss of cartilage, infiltration by many polymorphonuclear neutrophils, and the marked ingrowth of fibrous tissue in the COT group. Sagittal and coronal diameters and cross-sectional areas were significantly affected more severely after a COT than after an ODT., Conclusion: Our new modification of percutaneous dilatational tracheostomy, named "open dilatational tracheostomy," was successfully applied to a small, growing animal model and showed more favorable and consistent healing of trachea compared with COT. Therefore, the authors' new tracheostomy procedure could be applied to children who require short-term tracheostomy at any age in clinical settings.

Objectives/hypothesis: Tracheostomy is a commonly performed operative procedure that has been described since 2000 B.C. The early indications for tracheostomy were for upper airway obstruction, usually occurring in young people as a result of an infectious process. Recently, tracheostomies are more commonly performed in the critically ill patient to assist in long-term ventilatory support. Granulation tissue at the stoma and the trachea has been described as a late complication resulting in bleeding, drainage, and difficulty with maintaining mechanical ventilatory support., Study Design: The present report is of an observational study of a newly implemented policy that required regular changing of tracheostomy tubes. Comparable groups of patients were compared before and after this procedural change to document complications. Data collection consisted of chart reviews of all admissions for 1 year before the policy change and the subsequent 2 years. Complication rates were compared using standard statistical techniques., Methods: A policy change was instituted that required all tracheostomy tubes to be changed every 2 weeks in conjunction with a detailed evaluation of the tracheostomy stoma. Charts were reviewed the year before the change in policy and in the subsequent 2 years to determine the incidence of granulation tissue requiring operative intervention., Results: The number of patients requiring surgical intervention secondary to granulation tissue showed a statistically significant decrease (P =.02). A review of policies and procedures from the six largest hospitals in southeastern Michigan had no recommendations for routine tracheostomy tube changes., Conclusions: A policy requiring a routine change of tracheostomy tubes results in fewer complications from granulation tissue. Tracheostomy tube changes to prevent granulation tissue and its complications.

Objective: To evaluate the stoma and surrounding insertion site for common laryngotracheal injury patterns after percutaneous dilational tracheostomy that may contribute to clinically significant tracheal stenosis., Study Design: Preliminary prospective cadaver study., Methods: A preliminary prospective cadaver study was performed in which percutaneous dilational tracheostomy (Ciaglia Blue Rhino kit) was placed in six fixed cadaveric specimens. Laryngotracheal segments were harvested. Two independent evaluators graded cadaver features and characteristic injuries in laryngotracheal specimens the tracheal site of stoma placement was identified. Cadaver features evaluated included gender, obesity, and ease of landmark identification. Mucosal and cartilage injuries were evaluated on a scale of 0 to 4, with 4 representing severe comminuted injuries beyond the intended stoma site., Results: Accurate prediction of tracheal placement was achieved in only three (50%) of the specimens. In the remaining cadavers, one stoma site was placed higher than intended (16%) and two sites were lower than intended (33%). Mucosal injury was most severe at the anterior internal surface of the trachea with all specimens sustaining tears beyond one tracheal ring (mean mucosal injury score, 3.5). Cartilaginous injury was severe in five of six specimens (83%) that sustained multiple comminuted injuries to two or more adjacent rings (mean cartilage injury score, 3.34). Cricoid comminutions and a posterior membranous tracheal wall injury were each found in one specimen., Conclusions: Laryngotracheal injuries found after percutaneous dilational tracheostomy in the study indicated that severe damage to mucosa and cartilage surrounding the intended stoma site occurs at the time of placement. These injuries may contribute to clinically significant tracheal stenosis preventing decannulation in patients undergoing percutaneous dilational tracheostomy. Two case studies that support this hypothesis are also presented.

Objectives/hypothesis: Early topical application of mitomycin to a laryngotracheal lesion may prevent or reduce laryngotracheal stenosis (LTS)., Study Design: Prospective controlled animal study., Methods: LTS was induced in 60 dogs randomly assigned to four groups. Controls received an immediate topical application of normal saline. The suction-control group received an immediate application of normal saline followed by suction of secretions on day 2. The mitomycin group received immediate application of 0.7 mL mitomycin (0.2 mg/mL). The repeat-mitomycin group received an immediate application of mitomycin and a second application on day 2, after secretions were suctioned. The laryngeal lumens were measured endoscopically at baseline, day 12, and day 21. Animals were euthanatized if stenosis approximated 95% or at day 21., Results: All dogs in the mitomycin groups survived to day 21, compared with 12 in the suction group and only 2 controls. No side effects of mitomycin were observed. At day 21, surviving controls had 85% and 95% stenosis. In the mitomycin group, median stenosis was 27% (interquartile range, 29% to 42%); in the repeat-mitomycin group, 30% (22% to 40%); and in the suction-control group, 84.5% (72.5% to 93.5%). The mitomycin group differed significantly from controls on day 12 (median difference = 85%, 95% CI = 80%-94%, P < .0001) and day 21 (difference = 63.9%, 95% CI = 58%-85%, P = .031)., Conclusion: A single topical application of mitomycin significantly reduces the severity of LTS in dogs. Reapplication after 2 days does not improve results. Prospective clinical studies are warranted to assess the efficacy in humans.

Tracheostomal stenosis after total laryngectomy is a frequently occurring nuisance to both the patient and the surgeon. Although many causes may contribute to the development of tracheostomal stenosis, operative technique seems to play a major role. The authors describe and explain their method of stomal construction. Over a 10-year period they have used the described method on 260 patients undergoing a total laryngectomy, with an incidence of tracheostomal stenosis of 6%.

The application of a rapidly vascularized epithelial equivalent that inhibits wound contraction would have great potential in the prevention and repair of tracheal stenosis. An animal model was developed to simulate the effects of circumferential tracheal injury and an autologous epithelial equivalent was created from a fibroblast-collagen matrix and subsequently implanted in the traumatized site in an attempt to prevent stenosis. Postinjury physiologic and histologic evaluation revealed near-normal mucosal flow analysis in the treated sites and an area of less than 20% stenosis versus 95+% in controls. This study's findings indicate that tracheal stenosis can be limited by the use of an epithelial equivalent.

A new technique for construction of the tracheostome at the time of total laryngectomy is described. It involves making an X-shaped incision on the lower skin flap and four slits on the divided trachea. The result is a serrated suture line at the tracheocutaneous junction. The incidence of stenosis in 116 patients who did not have this method of construction was 31%. Sex difference and previous irradiation was not found to be related to the occurrence of stenosis. Of 25 patients who had the new method of tracheostome construction, only one patient had to wear a tube until she died at 7 months. The rest, followed up for at least 9 months, did not have stenosis. It is concluded that this new method of tracheostome construction will reduce the incidence of stenosis.

A superiorly based tracheal flap raised from the anterior tracheal wall was rotated anteriorly and superiorly to be sutured to the subcutaneous tissues. A series of 16 tracheostomies were performed on mongrel dogs. The stenosing effects of conventionally performed operations were compared to those of the new method. Autopsy sections of the post-tracheostomy sites demonstrated a significant loss of anteroposterior diameter averaging 16.5% as compared to the original unoperated-on luminae. No signs of tracheal stenosis were found whenever the proposed new technique was employed. This technique seems applicable to patients in whom assisted ventilation is contemplated.

In order to further address the problem of tracheal stenosis, an animal model was created to simulate both local and regional tracheal injury. An epithelial equivalent created from a fibroblast-collagen matrix was used to attempt to either inhibit or lessen the degree of tracheal stenosis that was evident in animal models. Preliminary data appears to show that the epithelial equivalent is effective in limiting and perhaps even abolishing the development of tracheal stenosis.