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Objectives/hypothesis: Despite surgical advances, childhood tracheal stenosis is associated with high morbidity and mortality. Various tracheal scaffold strategies have been developed as the basis for bioengineered substitutes, but there is no consensus on which may be superior in vivo. We hypothesized that there would be no difference in morbidity and mortality between three competing scaffold strategies in rabbits., Study Design: Pilot preclinical study., Methods: Tracheal scaffolds were prepared by three methods that have been applied clinically and reported: preserved cadaveric ("Herberhold") allografts, detergent-enzymatically decellularized allografts, and synthetic scaffolds (nanocomposite polymer [polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU)]). Scaffolds were implanted into cervical trachea of New Zealand White rabbits (n = 4 per group) without cell seeding. Control animals (n = 4) received autotransplanted tracheal segments using the same technique. Animals underwent bronchoscopic monitoring of the grafts for 30 days. Macroscopic evaluation of tissue integration, graft stenosis, and collapsibility and histological examinations were performed on explants at termination., Results: All surgical controls survived to termination without airway compromise. Mild to moderate anastomotic stenosis from granulation tissue was detected, but there was evidence suggestive of vascular reconnection with minimal fibrous encapsulation. In contrast, three of the four animals in the Herberhold and POSS-PCU groups, and all animals receiving decellularized allografts, required early termination due to respiratory distress. Herberhold grafts showed intense inflammatory reactions, anastomotic stenoses, and mucus plugging. Synthetic graft integration and vascularization were poor, whereas decellularized grafts demonstrated malacia and collapse but had features suggestive of vascular connection or revascularization., Conclusions: There are mirror-image benefits and drawbacks to nonrecellularized, decellularized, and synthetic grafts, such that none emerged as the preferred option. Results from prevascularized and/or cell-seeded grafts (as applied clinically) may elucidate clearer advantages of one scaffold type over another., Level of Evidence: NA. Laryngoscope, 127:E449-E457, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Tracheal replacement for the treatment of end-stage airway disease remains an elusive goal. The use of tissue-engineered tracheae in compassionate use cases suggests that such an approach is a viable option. Here, a stem cell-seeded, decellularized tissue-engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. The graft represents the first cell-seeded tracheal graft manufactured to full good manufacturing practice (GMP) standards. We report important preclinical and clinical data from the case, which ended in the death of the recipient. Early results were encouraging, but an acute event, hypothesized to be an intrathoracic bleed, caused sudden airway obstruction 3 weeks post-transplantation, resulting in her death. We detail the clinical events and identify areas of priority to improve future grafts. In particular, we advocate the use of stents during the first few months post-implantation. The negative outcome of this case highlights the inherent difficulties in clinical translation where preclinical in vivo models cannot replicate complex clinical scenarios that are encountered. The practical difficulties in delivering GMP grafts underscore the need to refine protocols for phase I clinical trials. Stem Cells Translational Medicine 2017;6:1458-1464., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Stem cell-based tissue-engineered tracheas are at an early stage in their product development cycle. Tens of patients have been treated worldwide in predominantly compassionate use settings, demonstrating significant promise. This potentially life-saving treatment is complex, and the cost and its implications for such treatments are yet to be fully understood. The costs are compounded by varying strategies for graft preparation and transplant, resulting in differing clinical and laboratory costs from different research groups. In this study, we present a detailed breakdown of the clinical and manufacturing costs for three of the United Kingdom (UK) patients treated with such transplants. All three patients were treated under Compassionate Use legislation, within the UK National Health Service (NHS) hospital setting. The total costs for the three UK patients treated ranged from $174,420 to $740,500. All three patients were in a state of poor health at time of treatment and had a number of complexities in addition to the restricted airway. This is the first time a cost analysis has been made for a tissue-engineered organ and provides a benchmark for future studies, as well as comparative data for use in reimbursement considerations.

Hunter syndrome is a multisystem genetic disease in which a significant proportion of morbidity and mortality arise from respiratory dysfunction. Notably, tracheal abnormalities in Hunter syndrome can compromise clinical stability, and management is primarily supportive. We describe here the first successful implementation of aorto-tracheopexy in a 19-year-old patient as a surgical strategy to resolve progressive respiratory deterioration., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

There has been significant and exciting recent progress in the development of bioengineering approaches for generating tracheal tissue that can be used for congenital and acquired tracheal diseases. This includes a growing clinical experience in both pediatric and adult patients with life-threatening tracheal diseases. However, not all of these attempts have been successful, and there is ongoing discussion and debate about the optimal approaches to be used. These include considerations of optimal materials, particularly use of synthetic versus biologic scaffolds, appropriate cellularization of the scaffolds, optimal surgical approaches and optimal measure of both clinical and biologic outcomes. To address these issues, the International Society of Cell Therapy convened a first-ever meeting of the leading clinicians and tracheal biologists, along with experts in regulatory and ethical affairs, to discuss and debate the issues. A series of recommendations are presented for how to best move the field ahead., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Prosthetic materials, autologous tissues, cryopreserved homografts and allogeneic tissues have thus far proven unsuccessful in providing long-term functional solutions to extensive upper airway disease and damage. Research is therefore focusing on the rapidly expanding fields of regenerative medicine and tissue engineering in order to provide stem cell-based constructs for airway reconstruction, substitution and/or regeneration., Areas Covered: Advances in stem cell technology, biomaterials and growth factor interactions have been instrumental in guiding optimization of tissue-engineered airways, leading to several first-in-man studies investigating stem cell-based tissue-engineered tracheal transplants in patients. Here, we summarize current progress, outstanding research questions, as well as future directions within the field., Expert Opinion: The complex immune interaction between the transplant and host in vivo is only beginning to be untangled. Recent progress in our understanding of stem cell biology, decellularization techniques, biomaterials and transplantation immunobiology offers the prospect of transplanting airways without the need for lifelong immunosuppression. In addition, progress in airway revascularization, reinnervation and ever-increasingly sophisticated bioreactor design is opening up new avenues for the construction of a tissue-engineered larynx. Finally, 3D printing is a novel technique with the potential to render microscopic control over how cells are incorporated and grown onto the tissue-engineered airway.

Pulmonary artery slings are rare congenital anomalies seen only on the left side. The presence of right pulmonary artery (RPA) sling is extremely rare. We report a case of a RPA sling with a single lung associated with tracheal stenosis and its management., (© 2013 Wiley Periodicals, Inc.)

Congenital anomalies of bronchial division are extremely rare. Presence of complete cartilaginous rings in bronchial tree with co-existent bronchial division anomalies make surgical correction more challenging, and needs a well-structured surgical pathway. We report a case of complex airway pattern similar to Christmas-tree appearance with associated stenosis due to complete rings, treated by modified sliding tracheoplasty with a successful outcome.

Background: Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up., Methods: A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor β to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts., Findings: The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school., Interpretation: Follow-up of the first paediatric, stem-cell-based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research., Funding: Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Tracheomalacia associated with esophageal atresia (EA) is a well-known condition. However, complete absence of tracheal rings (TRs) is extremely rare. Our aim is to describe a novel triad of conditions and to discuss the best treatment. An expremature male operated for EA presented with severe respiratory distress. The diagnosis of absent cartilage rings, suspected on bronchoscopy, was confirmed by optical coherence tomography. The absence of TRs was localized to a short tracheal segment, and the carina trifurcated into right upper lobe, right intermediate, and left main bronchus. The patient was treated with resection and anastomosis with a completely satisfactory course. Absence of TRs was previously reported by us in 2 other cases, both with associated EA and trifurcation of the carina. One child was treated with tracheostomy and the other with a stent, but the outcome was far from optimal. The patient with tracheostomy eventually underwent resection and anastomosis with tracheostomy closure. Congenital absence of TRs is extremely rare. Although localized, it is responsible for severe symptoms owing to complete tracheal collapse and may be misdiagnosed as tracheomalacia. In our experience, it has been associated with EA and trifurcated carina. Our limited experience suggests resection of the abnormal segment and tracheal anastomosis as the best treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Slide tracheoplasty has become the surgical technique of choice for repair of congenital tracheal stenosis. Despite the initial reluctance regarding the ability of this "reconstructed" trachea to grow, the reduced morbidity and mortality have allowed slide tracheoplasty to be widely adopted. The aim of this study was to evaluate tracheal growth after slide tracheoplasty., Methods: This was a retrospective study. In follow-up bronchography performed 1, 6, 12, 18, and 24 months after slide tracheoplasty, we measured the cross-sectional areas of the midtrachea and distal trachea at each investigation and correlated the measurements with the anthropomorphic factors (body weight, height, and body surface)., Results: Fourteen patients were enrolled in this study. The midtracheal and distal tracheal cross-sectional areas significantly increased with time (p ≤ 0.0001). The average rates of midtracheal growth were 21.0 mm(2)year in the first 6 months and 8.0 mm(2)/year in the first 2 years, and the distal trachea grew 18.5 mm(2)/year and 8.4 mm(2)/year, respectively. Regression analysis showed that both the midtrachea and the distal trachea increase significantly with weight (r(2) = 0.257, p ≤ 0.0001), height (r(2) = 0.376, p ≤ 0.0001), and body surface area (r(2) = 0.315, p ≤ 0.0001). Balloon dilation did not significantly alter the tracheal growth in the first 2 years after slide tracheoplasty., Conclusions: Slide tracheoplasty does not inhibit tracheal growth. The reconstructed trachea grows faster in the first 6 months and slows in the following 18 months. There is a positive correlation between tracheal cross-sectional area and weight, height, and body surface area., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Prosthetic replacements, autologous tissue transfer and allografts have so far failed to offer functional solutions for the treatment of long circumferential tracheal defects and loss of a functioning larynx. Interest has therefore turned increasingly to the field of tissue-engineering which applies the principles and methods of bioengineering, material science, cell transplantation and life sciences in an effort to develop in vitro biological substitutes able to restore, maintain or improve tissue and organ function., Areas Covered: This article gives an overview of the tissue-engineering approach to airway replacement and will describe the encouraging results obtained so far in tracheal regeneration. The recent advances in the field of tissue-engineering have provided a new attractive approach towards the concept of functional substitutes and may represent an alternative to the shortage of suitable grafts for reconstructive airway surgery. We summarize fundamental questions, as well as future directions in airway tissue engineering., Expert Opinion: The replacement of active movement, as would be necessary to replace an entire larynx introduces another order of magnitude of complexity, although progress in this area is starting to bear fruit. In addition, the stem cell field is advancing rapidly, opening new avenues for this type of therapy.

Objective: The aim of the study is to assess the surgical outcome of slide tracheoplasty in patients with congenital tracheal stenosis and single lung., Methods: Pre, intra- and postoperative data were collected. Anatomy and associated anomalies were described., Results: Seven patients (median age 5 months; range 39 days-1 year) with single lung underwent slide tracheoplasty. Single right lung was present in four patients. Associated anomalies were present in four patients (56%) including vascular ring, left pulmonary artery (LPA) sling, VACTERL (abnormalities of the vertebrae, anus, cardiovascular tree, trachea, oesophagus, renal system, and limb buds) syndrome, atrial septal defect (ASD) and aberrant left subclavian artery. Six patients (85%) needed preoperative ventilation and two (28%) needed preoperative extracorporeal membrane oxygenation (ECMO). Median postoperative ventilation was 7 days (6-35 days). Two patients needed postoperative ECMO, one of whom required preoperative ECMO. Complications occurred in five patients (71%): reintubation due to pneumothorax, pneumonia and several tracheal dilatations due to recurrent tracheal stenosis, which was eventually stented. There was one hospital death in a patient, who could not be weaned off ECMO due to severe distal malacia. At a median follow-up of 16 months (7 days-7 years), all survivors are in good clinical condition and without additional stenting., Conclusion: Slide tracheoplasty can be performed in patients with single lung and tracheal stenosis with a good surgical outcome., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Long segment congenital tracheal stenosis (LSCTS), associated with complete tracheal rings, is a rare condition, difficult to manage and historically associated with high mortality rate. We report two pairs of identical twins all affected by LSCTS successfully treated by sliding tracheoplasty. All had severe respiratory distress. Three infants had left pulmonary artery (LPA) sling and one intra-cardiac malformation. Slide tracheoplasty was done under cardiopulmonary bypass, and cardiovascular malformations were corrected at the same time. One child needed plication of paralyzed right hemi-diaphragm and another distal tracheal Palmaz stent insertion due severe tracheobronchomalacia. All children are doing well during 6 months follow-up. Slide tracheoplasty seems to produce the same good early results in twins as for singletons with LSCTS.

Objective: To review our strategy for the treatment of patients with Type IV laryngotracheoesophageal cleft-a very rare congenital malformation., Methods: Retrospective review of nine cases of Type IV laryngotracheoesophageal cleft managed between October 1994 and January 2004 at Great Ormond Street Hospital for Children, London., Results: Three children were not operated upon (Group A) because of serious co-morbidity and parental decision not to opt for repair; they died at the ages of 2, 7 and 14 days, respectively. Six cases were repaired (Group B) at ages ranging from 2 to 53 days, all using an anterior cervico-thoracic approach. Two cases were operated upon using conventional ventilation, three using cardiopulmonary bypass and one using extracorporeal membrane oxygenation. There was no intra-operative mortality. The number of operative and diagnostic procedures varied from 4 to 37. Two operated cases expired at the ages of 11 days and 25 months; both were operated upon using cardiopulmonary bypass and had significant cardiac co-morbidity. Post-operative microlaryngoscopy and bronchoscopy showed dehiscence in the cleft repair ranging from 1mm to 2cm in five cases. This was observed at the distal end in three patients and just below the vocal cords in two cases. Three cases underwent further repair which was successful. The most recent case repaired using extracorporeal membrane oxygenation required less heparin when compared with those done on cardiopulmonary bypass and had the best post-operative result. Two patients were finally decannulated. The total duration of diagnostic and operative procedures ranged from 9 to 26h and 30min. The hospital stay in the operated cases varied from 9 days to 2 years 2 months 3 days, and their ICU stay ranged from 9 days to 10 months 7 days. All four of our patients with clefts which ended above the carina are alive after multiple repairs whereas all five cases with clefts extending all the way to the carina died (repair was attempted in two)., Conclusion: Early diagnosis and repair are essential for successful treatment of Type IV laryngotracheoesophageal clefts. We believe it is best to repair this defect via an anterior cervico-thoracic approach, with or without a median sternotomy, and extracorporeal membrane oxygenation is now our preferred method of gas exchange during such repair. The longest Type IV clefts extending all the way to the carina have the worst prognosis. The decision to operate or not should be based upon the associated co-morbidity and fully informed parental choice, since treatment entails significant morbidity and mortality.

Slide tracheoplasty has become the preferred technique for repair of long-segment congenital tracheal stenosis with complete tracheal rings. Complex morphological subtypes require technical modifications, which we present as follows.

Objective: Long-segment tracheal stenosis is rare, life-threatening, difficult, and expensive to treat. Management remains controversial. A multidisciplinary tracheal team was formed in 2000 to deal with a large number of children with airway problems referred for management. We review the effect of that service, comparing the era before and after the establishment of the multidisciplinary tracheal team., Methods: From January 1998 through January 2004, 34 patients with long-segment tracheal stenosis (21 patients with cardiovascular anomalies) underwent surgical intervention. Cardiopulmonary bypass was used in all operations. Before the multidisciplinary tracheal team, pericardial patch tracheoplasty with or without an autograft technique was the preferred method of repair. After the multidisciplinary tracheal team, an integrated care plan preferring slide tracheoplasty was initiated, correcting cardiac lesions simultaneously., Results: Before the establishment of the multidisciplinary tracheal team, pericardial patch tracheoplasty was performed in 15 of 19 patients. Twelve patients had a suspended pericardial patch tracheoplasty, 2 (17%) of whom died late after the operation. Of 3 patients who had had a simple unsuspended patch, 2 (67%) died early after the operation. Four patients were operated on with the tracheal autograft technique, 2 (50%) dying early in the postoperative period. After multidisciplinary tracheal team formation, in the era between 2001 and 2004, 15 patients were operated on with slide tracheoplasty, and there were 2 (13%) early postoperative deaths. A significant reduction in cost and duration of stay has been shown both in the intensive care unit and the hospital., Conclusion: Our data suggest that a formalized multidisciplinary team approach and a policy of primary slide tracheoplasty are beneficial in the management of children with long-segment tracheal stenosis.

We describe an unusual case of tracheo-aortic fistula, which occurred after tracheal surgery and tracheal stenting. The management of this complex case and the surgical technique used for repair are discussed and illustrated. Repair of the aortic arch was accomplished using a modified technique of regional low-flow perfusion, similar to that described for neonatal aortic arch reconstruction. This strategy allowed maintenance of cerebral, myocardial, and systemic perfusion during arch repair, thus avoiding total circulatory arrest.

OBJECTIVES Our study describes and analyses the results from aortopexy for the treatment of airway malacia in children. METHODS Demographic data, characteristics and preoperative, operative and outcome details, including the need for reintervention, were collected for children undergoing aortopexy between 2006 and 2016. RESULTS One hundred patients [median age 8.2 months, interquartile range (IQR) 3.3–26.0 months] underwent aortopexy. Sixty-four (64%) patients had tracheomalacia (TM) only, 24 (24%) patients had TM extending into their bronchus (tracheobronchomalacia) and 11 (11%) patients had bronchomalacia. Forty-one (41%) children had gastro-oesophageal reflux disease, of which 17 (41%) children underwent a Nissen fundoplication. Twenty-eight (28%) children underwent a tracheo-oesophageal fistula repair prior to aortopexy (median 5.7 months, IQR 2.9–17.6 months). The median duration of follow-up was 5.3 years (IQR 2.9–7.5 years). Thirty-five (35%) patients were on mechanical ventilatory support before aortopexy. Twenty-seven (77%) patients could be safely weaned from ventilator support during the same admission after aortopexy (median 2 days, IQR 0–3 days). Fourteen patients required reintervention. Overall mortality was 16%. Multivariable analysis revealed preoperative ventilation (P  = 0.004) and bronchial involvement (P  = 0.004) to be adverse predictors of survival. Only bronchial involvement was a predictor for reintervention (P  = 0.012). CONCLUSIONS Aortopexy appears to be an effective procedure in the treatment of children with severe airway malacia. Bronchial involvement is associated with adverse outcome, and other procedures could be more suitable. For the treatment of severe airway malacia with isolated airway compression, we currently recommend aortopexy to be considered. [ABSTRACT FROM AUTHOR]

Congenital tracheobronchial stenosis is a rare disease characterized by complete tracheal rings that can affect variable lengths of the tracheobronchial tree. It causes high levels of morbidity and mortality both due to the stenosis itself and to the high incidence of other associated congenital malformations. Successful management of this complex condition requires a highly individualized approach delivered by an experienced multidisciplinary team, which is best delivered within centralized units with the necessary diverse expertise. In such settings, surgical correction by slide tracheoplasty has become increasingly successful over the past 2 decades such that long-term survival now exceeds 88%, with normalization of quality of life scores for patients with non-syndrome-associated congenital tracheal stenosis. Careful assessment and planning of treatment strategies is of paramount importance for both successful management and the provision of patients and carers with accurate and realistic treatment counseling. [ABSTRACT FROM AUTHOR]

Aortopexy is the treatment of choice for clinically significant tracheobronchomalacia from external vascular compression. When a marked chest depression is present, aortopexy may be less effective. We report 2 patients with pectus excavatum and vascular compression of the trachea who, despite their young age, benefited from combined Nuss bar insertion and aortopexy. [Copyright &y& Elsevier]