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J Thorac Dis
Non-malignant and malignant obstruction of the tracheal airway causes significant morbidity and mortality. With increased use of artificial airways, benign and iatrogenic complications are increasing. A tracheal stenosis that is less than 5 cm in length can be resected with end-to-end anastomosis. Longer tracheal lesions can be treated in a palliative way by placement of a stent to secure airway lumen patency. The management of tracheal defects is an evolving field. Tracheal transplantation and tracheal regeneration may bring major treatment advances to cases with long-segment tracheal involvement. This review examines the current possibilities and future prospects in the area of tracheal transplantation and regeneration.
Trachea; regeneration; revascularization; transplant.
Conflict of interest statement
Conflicts of Interest: The authors have no conflicts of interest to declare.
Prosthetic replacement: airway versus vascular conduits. (A) Blood vessel prosthesis. Endothelialization of the luminal surface of vascular grafts occurs only 1 to 2 cm into the graft from the anastomotic site. These endothelial cells are derived from adjacent, native endothelium and they enable the anastomosis to heal; (B) airway prosthesis. In the respiratory tract, the flow of inspired air will lead to bacterial contamination and wound breakdown at the anastomosis. The respiratory epithelium will not grow over the prosthesis-airway anastomosis; (C) airway prosthesis wrapped in vascularized tissue. A prosthesis may act as a temporary airway stent when it is wrapped by well-vascularized tissue (e.g., omentum). The vascularized tissue around the prosthesis may temporarily avoid the complications of wound breakdown at the anastomotic sites.
Palliative treatment of long-segment tracheal defects.
Vascularized and de-vascularized trachea. (A) In the healthy native trachea, the blood supply is ensured by a network of small blood vessels penetrating the trachea between the cartilage rings. Successful grafting (green-colored arrow) of a segment of the trachea requires the segment to have an intact and independent blood supply; (B) prelevation of a tracheal segment inevitably leads to interruption of its blood supply. Successful transplantation (red-colored arrow) requires restoration of an adequate blood supply, as in A. This is extremely difficult; (C) de-vascularized tracheal segments can become revascularized in a heterotopical position. The cartilaginous trachea can undergo progressive revascularization when wrapped with well-vascularized tissue. In humans, revascularization of the membranous trachea will be difficult because the trachealis muscle forms a barrier for mucosal revascularization. We learned that heterotopic tracheal revascularization occurs in a safer way after excision of the membranous trachea.
Overview of our experience in tracheal allotransplantation. Eight transplants were used in six patients. Two of the initial transplants were lost after withdrawal of immunosuppressive therapy. Important is to make partial incisions of the intercartilaginous (I.C.) ligaments at the time of forearm implantation to preserve the viability of the transplant after cessation of immunosuppressive drugs.
Orthotopic tracheal revascularization. The approach to heterotopic revascularization is shown. The forearm skin is incised and dissected away from the underlying fascia and subcutaneous tissue. After removal of the membranous part (A), the trachea is wrapped with the radial forearm fascia (B) and the forearm skin flaps are sutured to the incised trachea. Revascularization can be achieved by the outgrowth of capillary buds from the native vascularized tissue to unite with capillaries in the adventitia of the trachea (C). This link-up should be well advanced by the third day (D).
Tracheal revascularization and mucosal regeneration. (A) The cartilaginous trachea is revascularized (red arrows) by the surrounding tissues through the intercartilaginous ligament; (B) regeneration of the donor respiratory epithelium occurs simultaneously with the revascularization process; (C,D) partial incision of the intercartilaginous ligament (inset) will bring the recipient blood vessels closer to the donor submucosal capillaries, which will result in advancing of the revascularization process.
Importance of intercartilaginous incisions and of recipient mucosa. (A) After tracheal allograft revascularization and mucosal regeneration, recipient buccal mucosa can be introduced into the midportion of the allotransplant. A mucosal defect is created in the central part of the transplant and the midportion is grafted with a full-thickness mucosal graft from the recipient’s buccal area; (B) after withdrawal of immunosuppressive drugs: immunologically-induced lymphocytes attack the microcirculation. Inflammatory vascular infiltrates will lead to thrombosis of donor-derived blood vessels and to necrosis of the mucosal layer. The intercartilaginous ligaments were observed to be acting as a barrier to the ingrowth of recipient blood vessels. The intercartilaginous incisions will allow for ingrowth of recipient blood vessels into the submucosal space of the transplant. These newly formed recipient blood vessels will allow the recipient mucosal lining in the midportion of the transplant to survive immunosuppressant withdrawal. The surviving recipient mucosal graft will allow for secondary healing of the areas of donor epithelial lining that underwent necrosis (yellow arrows).
Allotransplantation of a long-segment tracheal stenosis. Orthotopic transplantation of a tracheal transplant to resolve a long-segment (6 cm) airway stenosis is illustrated. An eight cm long tracheal allotransplant is implanted at the forearm. During the first weeks the luminal site of the transplant is protected by the application of fibrin glue. After revascularization, a buccal mucosa graft from the recipient can be applied to the midportion of the transplant to allow for a safe withdrawal of immunosuppressive drugs. The long-segment tracheal stenosis is incised longitudinally (double arrow). After full revascularization and mucosal regeneration have been achieved, the tracheal allotransplant is transplanted from the forearm to the airway defect on a radial vascular pedicle. The radial blood vessels are sutured to the neck vessels to facilitate revascularization. The cartilaginous trachea is sutured into the airway defect to restore the concavity of the airway lumen. Withdrawal of immunosuppressive therapy can start 1 year after orthotopic transplantation.
Patient with low-grade chondrosarcoma. Tracheal allotransplant at time of forearm implantation with I.C. incision (A) and after full revascularization with a recipient buccal mucosa graft at it’s midportion (B). Tumor involvement visible on a coronal CT scan image (C). The airway lumen is bridged by a silicone stent. The degree of resection is indicated with white, two-headed arrows. The lengths of the tracheal resection were 9 cm (right) and 6 cm (left) (scale =1 cm). After 4 months, the tumor could be resected and the tracheal allotransplant was used to repair the laryngotracheal defect (D).
CT scan after orthotopic transplantation and after withdrawal of immunosuppressive drugs. A CT scan 2 years after orthotopic transplantation and 6 months after cessation of all immunosuppressive therapy is shown. Note the absence of cartilage calcification in the allotransplant (scale =1 cm). (A) Sagittal reformatted CT scan; (B) axial CT scan at laryngeal level; (C) axial CT scan at level of cervical trachea; (D) coronal reformatted CT scan.
Implantation of two tracheal allografts for circumferential airway repair. The full length of the trachea and main bronchi can be used for allotransplantation. Two cartilaginous tracheal segments with a length of 9 cm may be implanted at two forearm sites. By suturing the two allotransplants together, a tube may be created for circumferential airway repair.
Circumferential airway repair. The first transplant is used to restore the posterior and lateral walls of the airway. A part of the forearm skin can be included as a temporary reconstruction of the anterior wall. In a second operation, the second transplant can be used to replace the forearm skin and to further augment the airway lumen.
Regeneration of airway tissue. The basement membrane of the mucosal layer supports a pseudostratified epithelium, the surface layer of which is columnar and ciliated, with deeper layers of oval or rounded basal cells. A superficial epithelial wound can heal through regeneration of the surface epithelium. Tissues with high proliferative capacity renew themselves continuously and can regenerate after injury above the basal membrane through proliferation and differentiation of basal cells.
How the engineered trachea was represented. (A) De-vascularized native trachea; (B) as a first step towards a presumed ‘stem-cell engineered regenerated trachea’, a detergent is used to destroy all viable cells, leaving a scaffold of connective tissue; (C) a ‘stem-cell engineered regenerated trachea’: it is hypothesized that stem cells penetrate the connective tissue and subsequently regenerate cartilage, blood vessels and respiratory mucosa. This presumed regenerated trachea is implanted without restoration of any blood supply (red-colored arrow); (D) it is hypothesized that stem cell-mediated re-cellularization of a synthetic scaffold may also lead to a fully regenerated trachea that can be transplanted inside the airway (red-colored arrow).
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