Review Article
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Prefabrication and Prelamination Strategies for the Reconstruction of Complex Defects of Trachea and Larynx M. Den Hondt, MD1
P. Delaere, MD, PhD2
1 Department of Plastic and Reconstructive Surgery, KU Leuven
University Hospitals, Leuven, Belgium 2 Department of ENT, Head and Neck Oncology, KU Leuven University Hospitals, Leuven, Belgium
Address for correspondence Jan Jeroen Vranckx, MD, PhD, Department of Plastic and Reconstructive Surgery, KU Leuven University Hospitals, 49 Herestraat, B-3000 Leuven, Belgium (e-mail: [email protected]).
J Reconstr Microsurg 2014;30:145–152.
Abstract
Keywords
► prefabrication ► prelamination ► trachea reconstruction ► larynx reconstruction ► trachea transplantation
Complex tracheal and laryngeal defects can be reconstructed using prelamination and prefabrication techniques. Three clinical situations are described in detail in the article. In short segment restenosis defects within scarred surroundings, we restore the fibrocartilaginous defect with a radial forearm fascia flap prelaminated with buccal mucosa or cartilage. This provides a newly vascularized inner lining to the tracheal defect and restores the tubular convexity. For long segment defects we need a technique that can withstand respiratory forces. We use a heterotopic prefabrication strategy to vascularize a tracheal allograft wrapped in forearm fascia. Chimerism is created by replacing donor respiratory epithelium with buccal mucosa of the recipient. After orthotopic transfer, this chimerism allows immunosuppression to be tapered and stopped when bronchoscopy shows mucosal integrity of the new trachea, since the recipient epithelium replaces the allogeneic inner tracheal lining by means of a chronic rejection process. A distinct situation occurs after resection of a unilateral larynx tumor, which usually results in a total laryngectomy with loss of both vocal cords, since reconstruction of the hemilarynx is considered too complex. First, we prefabricate a nearby four-ring autologous tracheal segment using radial forearm fascia. In a second stage, this orthotopically vascularized trachea restores the laryngeal structure with the aim to conserve one vocal cord and thus speech. Orthotopic and heterotopic prelamination and prefabrication strategies offer efficient and reproducible solutions for the restoration of challenging short and long segment tracheal defects, as well as unilateral laryngeal defects. The series in this review article are based on previous studies and case reports. The level of evidence is III—“Study of nonconsecutive patients, without a universally applied gold standard: case-control study”.
At first sight, the trachea seems a simple rigid conduit for air passage. However, the trachea has a complex anatomy to fulfill this task. The fibrocartilaginous structure gives support to maintain the airway lumen and provides vertical elasticity for deglutition, speech and motion of the neck. The intercartilaginous ligaments allow for entrance of blood vessels to
perfuse the mucosal lining.1,2 The structure of the larynx is even more complex, since the vocal cords are suspended in a mucosa-lined fibrocartilaginous framework that has a particular hollow shape to provide for resonance and breathing. Reconstruction of defects of the trachea and larynx is demanding due to these features. We use prelamination
received September 23, 2013 accepted after revision October 17, 2013 published online January 7, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1361928. ISSN 0743-684X.
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J. J. Vranckx, MD, PhD1
Trachea and Larynx Reconstruction with Prefabrication and prefabrication strategies to vascularize autologous trachea segments in an orthotopic position and allogeneic trachea in a heterotopic position to restore complex tracheal and laryngeal defects.
Short and Long Segment Defects of the Trachea Considering the high risk of anastomotic failure, reapproximation of the neighboring tracheal ends cannot be performed safely if the defect is longer than 5 cm or even shorter in a scarred environment.3,4 To ensure a reliable restoration, the gap resulting from removal of the stricture should be filled with vascularized tissue that restores the inner mucosal lining and supports the fibrocartilaginous structure of the trachea.5–7 Bridging the defect after resection of a long segment tracheal stenosis imposes great challenge to our current knowledge. Conventionally, these lesions are treated by stent placement, to temporarily support the airway lumen. However, palliative stenting subjects the patient to significant morbidity such as stagnation of secretions causing persistent coughing and chronic airway infections, as well as recurrent formation of granulation tissue and subsequent obstruction, requiring repetitive laser treatment.2,8 Long-term adequate airway control with improved quality of life is mandatory for these patients and can only be obtained by providing an equally long mucosa-lined vascularized fibrocartilaginous framework. The human body offers no appropriate autologous replacement tissue that mimics all tracheal properties. Treatment options may focus on generating a substitute for the fibrocartilaginous framework by decellularization protocols on bovine or human donor trachea.9,10 However, the key element in primary healing of the trachea is supplying a well vascularized inner mucosal layer to an equally well vascularized flexible fibrocartilaginous framework. So far tissue engineering techniques cannot meet these requirements in a reproducible and predictive manner.11 Strategies using a framework of rib cartilage wrapped in vascularized tissue, but without inner mucosal lining, or a synthetic outer scaffold as cartilaginous replacement with an inner lining composed of a radial forearm free flap for longer tubular defects may be creative but cannot replace the specific hollow and tubular architecture of the mucosa-lined trachea required for appropriate function withstanding the respiratory forces and often end up with a permanent tracheostome.12 An allogeneic donor trachea supplies the required mucosa-lined fibrocartilaginous framework. Though, unlike other solid or composite organ transplants, the trachea only has an intrinsic segmental blood supply with vessels, which are too small to allow for direct microvascular transfer. Moreover, the fibrocartilaginous framework may elicit a low immunologic response, but the inner mucosal lining is destined for immunologic reaction since it is its duty protecting the inner tissues from the toxic elements in air that insufflates the windpipe. 2,8 Therefore, we use a preliminary prefabrication step to vascularize an allogeneic windpipe in a heterotopic position under temporary immunosuppression. Journal of Reconstructive Microsurgery
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Hemilaryngectomy for Unilateral Cancer of the Larynx Accepted treatment modalities for laryngeal cancer are radio(chemo)therapy and surgery. Even a unilateral advanced tumor on one vocal fold is usually treated with a total laryngectomy since the reconstruction of a hemilarynx to spare one vocal cord is considered to be very complex.13 However, every attempt should be made to avoid total laryngectomy since the loss of speech and the need of a permanent tracheostoma dramatically change the quality of life of those patients. The technique for extended hemilaryngectomy is designed to allow for functional treatment of lateralized glottic cancer with subglottic extension (T2, T3) and for lateralized chondrosarcomas of the cricoid cartilage. The aim of the reconstruction is to restore the extended hemilaryngectomy defect and to obtain morphology after reconstruction that is comparable to the vocal fold paralysis in the paramedian position.14 Because of its proximity to the larynx, the fibrocartilaginous structure of the trachea and its inner mucosal lining represent excellent donor tissue. For a one-stage reconstruction by simple upward advancement of 4 cm of trachea, a dissection from the surrounding tissues over approximately 8 cm is necessary. Consequently, this segment will have its extrinsic blood supply interrupted. Vascularity will further diminish after modification of the upper 4 cm of membranous trachea to create the convex patch and by placement of a temporary tracheostomy at the anterior wall. Even in nonirradiated cases, advancement of such a large tracheal segment would inevitably lead to patch necrosis. Therefore, we use an orthotopic prefabrication step to vascularize a segment of four tracheal rings.
Methods and Results Orthotopic Prelamination for Short Segment Stenosis of the Trachea To treat short segment stenosis of the trachea, we previously employed a two-stage prefabrication strategy, using the radial forearm fascia as a vascular carrier.7 An H-shaped incision in the forearm is made and the skin is dissected medially and laterally to expose the radial pedicle. The auricular cartilage was sutured on the radial forearm fascia (►Fig. 1). Because of the intrinsic thickness of the cartilage patch, a prefabrication step in situ is required to vascularize the patch before orthotopic transfer 2 weeks later. Once revascularized and transferred into the tracheal defect, mucosa will migrate over the perichondrium of the cartilage patch if we are dealing with a short segment defect. Our actual protocol consists of a 1-step orthotopic prelamination procedure. Thin buccal mucosa is sutured onto the radial forearm fascia (►Fig. 2). After microvascular transfer of the construct to the tracheal defect, a soft stent is inserted to provide for adequate rigidity. After 4 months, the inner mucosal lining is restored and the stent can be removed, leaving a stable tracheal lumen (►Figs. 3, 4).
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Fig. 1 Two-stage prefabrication procedure for short segment tracheal stenosis. (A) A radial forearm fascia flap is procured and used as a vascular carrier. (B) Auricular cartilage is sutured on the radial forearm fascia. The skin is closed on top. After the 2-week prefabrication step to vascularize the cartilage grafts, the orthotopic transfer to the trachea defect is performed. The distal skin monitor flap is sutured in the neck after closure.
Heterotopic Prefabrication of a Tracheal Allotransplant for Long Segment Stenosis of the Trachea A tracheal segment of a human donor (►Fig. 5) is sutured onto the forearm and wrapped with radial forearm fascia overlying the radial vascular pedicle.2 The posterior membranous trachea is resected, creating a horseshoe-shaped construct that can be monitored easily on the forearm. Triple immunosuppression is started following earlier established protocol.2 On a weekly base, the dressing is opened, the trachea cleaned and vascularity of the inner mucosa monitored. After stabilization of the graft, buccal mucosal patches of the recipient are used to replace donor epithelial lining, creating a chimeric mucosal lining of donor and recipient cells. Aim is to gradually replace the allogeneic inner lining, which is prone to immunologic rejection. After 3 months, the long stenotic tracheal segment is resected and orthotopic transfer of the prefabricated donor trachea takes place. Microvascular anastomosis is performed on the neck vessels. A temporary tracheostoma is used and removed once the patient is stable. Immunosuppression is given for 12 months. Tapering starts after bronchoscopic and histologic controls. Once inner mucosal lining and viability of the construct are concealed, immunotherapy is stopped.15 Ventilation perfusion scan, bronchoscopy and computed tomography (CT) scans are used to assess functional outcome.
Vranckx et al.
Fig. 2 One-stage prelamination procedure for short segment tracheal stenosis. (A) Thin buccal mucosa is sutured on the radial forearm fascia flap, which serves as the vascular carrier. (B) The prelaminated flap is sutured into the defect on the trachea, with the mucosa patch facing inward in an intraluminal position. A temporary laryngeal stent will prevent recollapse during the healing phase.
Orthotopic Prefabrication of Trachea for the Reconstruction of Hemilaryngectomy Defects For T3 glottic cancer, an extended hemilaryngectomy is performed. The tumor is resected with inclusion of the anterior commissure and half of the cricoid cartilage (►Figs. 6, 7). The ipsilateral thyroid lobe and tracheoesophageal lymph nodes are removed as well as the lymph nodes at level II, III and IV of the neck. Only tumors without extension to the supraglottic area are included in this protocol.16,17 Subsequently a radial forearm flap, with a proximal fasciocutaneous and a distal fascial component, is procured (►Fig. 6A to C). The fascial paddle is wrapped around the upper 4 cm of cervical trachea. Two sutures, placed at the lateral side of the defect between epiglottis and aryepiglottic fold, bring the aryepiglottic fold in a midline position posteriorly. The fasciocutaneous paddle is used to temporarily close the extended hemilaryngectomy defect. After microsurgical anastomosis of the radial vascular pedicle to the neck vessels, the flap and the pedicle are covered with an polytetrafluoroethylene (ePTFE) membrane to prevent adhesion formation. An inferolateral corner of the fasciocutaneous segment is Journal of Reconstructive Microsurgery
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Trachea and Larynx Reconstruction with Prefabrication
Trachea and Larynx Reconstruction with Prefabrication
Vranckx et al. modeled and transferred upward into the laryngeal defect. During the second stage, the microvascular pedicle of the radial forearm flap remains intact (►Fig. 7 A to C). After the first operation, the radial forearm fasciocutaneous flap restores the sphincter function of the larynx. Swallowing of solids and liquids is possible after 1 week and speaking is possible during finger occlusion of the temporary tracheostomy. After the second operation, the tracheal patch and the vascularized forearm flap succeed in restoration of the sphincteric and respiratory function. Hand-free speech is possible after closure of the tracheostoma 6 weeks after definitive reconstruction. Voice sounds natural and moderately hoarse.
Discussion
Fig. 3 Drawing of the reconstruction of the trachea defect with a prelaminated radial forearm flap with buccal mucosa. (A) Sagittal view of the reconstructed area: The prelaminated flap with buccal mucosa restores the inner mucosal lining. (B) Axial view: The temporary silicone stent is visible in the center. The vascularized patch of radial forearm fascia and buccal mucosa graft covers the defect. After 3 months the stent is removed. By then the inner mucosal lining has been restored. The loss of airway lumen after stent removal is minimal in limited defects.
The term flap prefabrication was introduced by Yao in the early 1980s19 but the principle of neovascularization by using a vascular carrier to generate a new axial blood supply in tissues goes back to the 1930s.20 Prelamination was defined by Pribaz and Guo21 in 1994 and refers to the process of bonding of distinctive layers, creating a novel anatomic threedimensional laminated structure, without interfering with the native axial blood supply.22 Both prefabrication and prelamination alter the existing anatomical features of tissues and can be considered as a form of “in situ tissue engineering.” Both strategies are used in difficult reconstructions where conventional methods are not available,23 such as for the reconstruction of complex defects of trachea and larynx.
Reconstruction of Tracheal Defects Reconstruction of Short Segment Stenosis of the Trachea
sutured onto the skin of the neck as microsurgical monitoring flap (►Fig. 6 D to 6). After 4 months a second look at the section margins is performed. If histology confirms absence of tumor recurrence, the definitive reconstruction is initiated.18 The ePTFE membrane is removed and the skin paddle is deepithelialized to serve as posterior bulk. The fascia-enwrapped segment of revascularized trachea is isolated, re-
Segmental tracheal resection with end-to-end anastomosis is the treatment of choice for a stenosis encompassing less than 50% of the tracheal length.1 However, traction or tension on the proximal and distal tracheal segment may lead to local necrosis, leakage and fistulization. Scarring due to previous interventions may limit a tensionless closure.3,6 Augmentation of the tracheal lumen by inserting locoregional or distant tissue is necessary when primary closure is not possible, as in
Fig. 4 Computed tomography scans of restenosis and tracheoplasty. (A) Scan at the stenotic site. (B) View after reconstruction with the mucosa prelaminated radial forearm free flap. The silicone stent is visible. (C) CT scan after removal of the silicone stent. Journal of Reconstructive Microsurgery
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preferred tissue combination for the treatment of an airway stenosis in which segmental resection and primary closure is impossible.7
Fig. 5 (A) A donor trachea has been prefabricated on the radial forearm, wrapped in forearm fascia overlying the radial vascular pedicle. A patch of ePTFE protects the allograft. (B) Overview of the tracheal allotransplantation procedure. A donor trachea is wrapped by radial forearm fascia in the forearm in heterotopic position. Buccal recipient mucosa replaces the posterior membrane and patches of allogeneic respiratory epithelium of the donor trachea. After prefabrication the vascularized trachea is transferred to the neck orthotopically. Immunosuppression is stopped when the trachea is in place and bronchoscopy shows well vascularized inner mucosal lining within the tracheal allogeneic framework.
cases of restenosis after previous resection.5 The most frequently harvested reconstructive tissues include cartilage grafts, pericardium and muscle flaps, used as a carrier for skin, periosteum, or bone.4 Since these donor tissues all lack one or more features for optimal tracheal repair, a stable outcome cannot be warranted. Our first protocol was based on an auricular cartilage framework. Whereas bare cartilage undergoes avascular necrosis when directly exposed to the airway lumen,6 we obtained a vascularized construct by means of prefabrication.7 The cartilage is sutured onto a vascularized fascial layer, such as the radial forearm fascia with its intrinsic blood supply. After 2 weeks, ingrowth of blood vessels is complete and the orthotopic transfer can be performed. More recently, we use a one-stage prelamination strategy with a mucosal patch with similar size as the defect, in combination with a temporary silicone stent for 4 to 6 weeks that will prevent prolapse of the mucosa-lined fascia and collapse of the incised and expanded airway.7 The mucosal lining prevents the crusting and desquamation seen when using skin grafts. There is a minor loss in curvature using this one-stage mucosa laminated strategy but without clinical impact if the defect is less than 40% of the tubular curvature. Mucosa-lined fascia, therefore, is currently the
To treat long airway defects, we need more structural support than provided by a prelaminated flap. However, there are no autologous donor tissues available to restore the mucosalined elastic cartilaginous framework. An avascular tissueengineered trachea without inner mucosal lining would be unsuitable for use. The bare tube would be exposed to the airway lumen and to continuous movements during respiration, swallowing, and coughing, preventing ingrowth of the surrounding tissue. Without intrinsic vascularization, scar tissue will be generated.9 Transplantation of an allogeneic trachea brings the required mucosa-lined fibrocartilaginous framework. However, although the vascular requirements of the cartilaginous framework are low and cartilage elicits a limited immunologic rejection, the inner mucosal lining needs a significant vascular supply and its immunologic response is as strong as for regular skin. Since the segmental blood supply to the trachea makes it unsuitable for direct revascularization, most previous attempts at tracheal transplantation have been performed after indirect revascularization, which also avoids the exposure to the bacteria-colonized air. Rose et al reported the first allogeneic tracheal transplantation in a human.10 The donor trachea was implanted heterotopically in the sternocleidomastoid muscle of the recipient and was transferred to the orthotopic position 3 weeks later. The recipient received no immunosuppressive therapy and the report did not document the viability of the allograft or the long-term outcome. Klepetko et al wrapped a tracheal allograft in the omentum of a patient who received a lung transplant from the same donor. Its viability was documented after 60 days of heterotopic revascularization.24 Indirect revascularization of a donor trachea with recipient tissue perfused by a well-defined vascular pedicle is perfectly feasible, as demonstrated by successful outcome in laboratory animals and humans.8,25 After initial prefabrication, a microvascular transfer of the construct can be performed.14 We reconstructed a long-segment tracheal defect in a patient by using an allograft that was revascularized in first stage by heterotopic wrapping in radial forearm fascia.2 Immunosuppressive therapy was necessary during the prefabrication step for establishing connections between the donor’s capillary network around the trachea and the recipient’s fascial blood vessels. This occurred quickly enough to maintain viability of the cartilaginous trachea. However, unlike in the animal model,8 the posterior membranous trachea underwent avascular necrosis. The necrotic segments were debrided and replaced with buccal mucosa. The recipient buccal mucosa grew progressively over the lumen of the cartilaginous tracheal transplant, creating a chimeric patchwork of donor epithelium and recipient buccal mucosa, as visualized by fluorescent in situ hybridization (FISH). Endothelial and respiratory cells originating from the donor disappeared shortly after withdrawal of immunosuppressive therapy. The immunologic rejection occurred silently because of the Journal of Reconstructive Microsurgery
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Fig. 6 Stage 1: (A) The resection specimen after hemilaryngectomy. (B) The hemilaryngectomy defect preoperatively. In white the ePTFE patch that will cover the fascia flap and vascular pedicle of the prefabricated trachea segment. The tracheal tube assures controlled preoperative respiration. (C) Drawing of the hemilaryngectomy defect. In white the tracheal segment that will be wrapped and prefabricated with the vascularized F. (D) Harvest of the FC and F radial forearm free flap. (E) The FC segment is used to temporarily close the hemilarynx defect and the F segment to wrap and prefabricate the trachea. A microvascular anastomosis is performed on the neck vessels. Usually we perform an end-to-end arterial anastomosis on the inferior thyroid artery and an end-to-side anastomosis on the internal jugular vein; (F) in white the area of resection. The white dots indicate the closure of the aryepiglottic area to recreate the sphincter. (G) and (H) Situation at the end of the first stage. Mark the monitor triangle at the inferolateral FC border and the ePTFE sheet that covers the fascia flap to avoid adhesions in preparation for the second stage. F, fascia; FC, fasciocutaneous.
repopulation of the donor tissue by the recipient’s surrounding vascular network and buccal mucosal cells. The viability of the tracheal cartilage was maintained after all immunosuppressive drugs had been discontinued. There is a meticulous balance between the speed of formation of neovascular connections and the oxygen requirements of the allogeneic Journal of Reconstructive Microsurgery
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trachea. The oxygen requirements of the mucosal lining are high.15 So far, five patients have been treated with seven allogeneic tracheal transplants with variable outcomes.15 Limiting factors remain the speed of revascularization of the inner mucosal lining of the tracheal transplant and the duration of the immunosuppressive therapy. If considering an
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Fig. 7 Stage 2: (A) The prefabricated trachea is opened horseshoe-shaped and remodeled to match the hemilaryngeal defect. The initial fasciocutaneous segment is de-epithelialized and serves as posterior bulk. In white the ePTFE sheet. (B) The hemilarynx defect is restored with the prefabricated trachea segment. In all these steps the microvascular pedicle of the microanastomosis of the first stage remains intact. (C) A combination of radial forearm skin and tracheal autotransplant gives a reconstruction against the midline posteriorly at the level of the vocal fold, while a small convexity is provided anteriorly by the tracheal autotransplant.
allogeneic tracheal protocol for low grade oncologic resections, the duration of immunosuppression becomes even more essential. Further studies should indicate which strategies are useful to enhance the neovascularization process in a clinical setting. We currently investigate the impact of blood originated endothelial cells (BOECs)—to enhance and accelerate the vascularization process of the inner mucosal lining.26,27 The BOECs can be procured from an autologous intravenous blood sample. Cell cultivation of autologous ciliated epithelium may also facilitate the quality and speed of re-epithelialization. Gentle decellularization protocols may retrieve more allogeneic epitopes while leaving the structural support of a donor trachea intact. We believe that a progressive integration of tissue engineering principles into the prefabrication allogeneic trachea model represents the future of trachea and larynx repair.
Reconstruction of the Hemilarynx After hemilaryngectomy for a unilateral larynx cancer, Zur and Urken transferred the trachea pedicled on the thyroid artery and vein with the adjacent thyroid gland in a single stage.28 However, there is an inherent risk of occult metastases to the thyroid gland and the paratracheal lymph nodes, which are commonly seen when there is significant subglottic extension. Therefore, to generate a revascularized autologous tracheal segment, a two-stage prefabrication procedure is required. We reported a modification of the operative sequence compared with our initial procedure. In the first series of patients, we performed the prefabrication of a four-ring tracheal segment by wrapping it with a radial forearm fascia flap.16,18 The prefabrication step took 2 weeks. In a second stage the tumor was resected and the hemilarynx was restored with the prefabricated tracheal construct. However, the prefabrication step in the first stage, before tumor resection in the second stage, could manipulate tumor cells and elicit spreading. The conversion of sequence, however, proved to be difficult: When the tumor is resected primarily, a hemilaryngeal defect exists at the time prefabrication of the trachea has only started.17,18 The hemilaryngeal defect, therefore, needs to be temporarily closed to allow breathing
and swallowing, while the prefabrication step takes place. Experience after reconstruction of 25 cases allowed us to modify the prefabrication sequence leading to optimal functional results without impairing oncological safety (n ¼ 65). Swallowing function recovers within a week after the first and second intervention, and the laryngeal respiratory function is fully regained after closure of the tracheostomy.17,18 Tracheal autotransplantation leads to optimal reconstruction of extended hemilaryngectomy defects.
Conclusion Orthotopic and heterotopic prelamination and prefabrication strategies offer innovative, efficient and reproducible solutions for the restoration of challenging short and long segment tracheal defects, as well as of unilateral laryngeal defects, previously considered almost inoperable. Gradually cell and tissue engineering strategies will be implemented to improve neovascularization and matrix formation and to introduce more autologous cultivated elements in context of allogeneic trachea transplantation.
Disclosure The authors have no commercial associations or financial disclosures to make. Margot Den Hondt has a scientific fund of the FWO Fonds Wetenschappelijk Onderzoek Vlaanderen. Presented in part at the American Society of Reconstructive Microsrugery, Naples 2013 and at the World Society of Reconstructive Microsurgery, Chicago 2013.
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Prefabrication and Prelamination Strategies for the Reconstruction of Complex Defects of Trachea and Larynx M. Den Hondt, MD1
P. Delaere, MD, PhD2
1 Department of Plastic and Reconstructive Surgery, KU Leuven
University Hospitals, Leuven, Belgium 2 Department of ENT, Head and Neck Oncology, KU Leuven University Hospitals, Leuven, Belgium
Address for correspondence Jan Jeroen Vranckx, MD, PhD, Department of Plastic and Reconstructive Surgery, KU Leuven University Hospitals, 49 Herestraat, B-3000 Leuven, Belgium (e-mail: [email protected]).
J Reconstr Microsurg 2014;30:145–152.
Abstract
Keywords
► prefabrication ► prelamination ► trachea reconstruction ► larynx reconstruction ► trachea transplantation
Complex tracheal and laryngeal defects can be reconstructed using prelamination and prefabrication techniques. Three clinical situations are described in detail in the article. In short segment restenosis defects within scarred surroundings, we restore the fibrocartilaginous defect with a radial forearm fascia flap prelaminated with buccal mucosa or cartilage. This provides a newly vascularized inner lining to the tracheal defect and restores the tubular convexity. For long segment defects we need a technique that can withstand respiratory forces. We use a heterotopic prefabrication strategy to vascularize a tracheal allograft wrapped in forearm fascia. Chimerism is created by replacing donor respiratory epithelium with buccal mucosa of the recipient. After orthotopic transfer, this chimerism allows immunosuppression to be tapered and stopped when bronchoscopy shows mucosal integrity of the new trachea, since the recipient epithelium replaces the allogeneic inner tracheal lining by means of a chronic rejection process. A distinct situation occurs after resection of a unilateral larynx tumor, which usually results in a total laryngectomy with loss of both vocal cords, since reconstruction of the hemilarynx is considered too complex. First, we prefabricate a nearby four-ring autologous tracheal segment using radial forearm fascia. In a second stage, this orthotopically vascularized trachea restores the laryngeal structure with the aim to conserve one vocal cord and thus speech. Orthotopic and heterotopic prelamination and prefabrication strategies offer efficient and reproducible solutions for the restoration of challenging short and long segment tracheal defects, as well as unilateral laryngeal defects. The series in this review article are based on previous studies and case reports. The level of evidence is III—“Study of nonconsecutive patients, without a universally applied gold standard: case-control study”.
At first sight, the trachea seems a simple rigid conduit for air passage. However, the trachea has a complex anatomy to fulfill this task. The fibrocartilaginous structure gives support to maintain the airway lumen and provides vertical elasticity for deglutition, speech and motion of the neck. The intercartilaginous ligaments allow for entrance of blood vessels to
perfuse the mucosal lining.1,2 The structure of the larynx is even more complex, since the vocal cords are suspended in a mucosa-lined fibrocartilaginous framework that has a particular hollow shape to provide for resonance and breathing. Reconstruction of defects of the trachea and larynx is demanding due to these features. We use prelamination
received September 23, 2013 accepted after revision October 17, 2013 published online January 7, 2014
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DOI http://dx.doi.org/ 10.1055/s-0033-1361928. ISSN 0743-684X.
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J. J. Vranckx, MD, PhD1
Trachea and Larynx Reconstruction with Prefabrication and prefabrication strategies to vascularize autologous trachea segments in an orthotopic position and allogeneic trachea in a heterotopic position to restore complex tracheal and laryngeal defects.
Short and Long Segment Defects of the Trachea Considering the high risk of anastomotic failure, reapproximation of the neighboring tracheal ends cannot be performed safely if the defect is longer than 5 cm or even shorter in a scarred environment.3,4 To ensure a reliable restoration, the gap resulting from removal of the stricture should be filled with vascularized tissue that restores the inner mucosal lining and supports the fibrocartilaginous structure of the trachea.5–7 Bridging the defect after resection of a long segment tracheal stenosis imposes great challenge to our current knowledge. Conventionally, these lesions are treated by stent placement, to temporarily support the airway lumen. However, palliative stenting subjects the patient to significant morbidity such as stagnation of secretions causing persistent coughing and chronic airway infections, as well as recurrent formation of granulation tissue and subsequent obstruction, requiring repetitive laser treatment.2,8 Long-term adequate airway control with improved quality of life is mandatory for these patients and can only be obtained by providing an equally long mucosa-lined vascularized fibrocartilaginous framework. The human body offers no appropriate autologous replacement tissue that mimics all tracheal properties. Treatment options may focus on generating a substitute for the fibrocartilaginous framework by decellularization protocols on bovine or human donor trachea.9,10 However, the key element in primary healing of the trachea is supplying a well vascularized inner mucosal layer to an equally well vascularized flexible fibrocartilaginous framework. So far tissue engineering techniques cannot meet these requirements in a reproducible and predictive manner.11 Strategies using a framework of rib cartilage wrapped in vascularized tissue, but without inner mucosal lining, or a synthetic outer scaffold as cartilaginous replacement with an inner lining composed of a radial forearm free flap for longer tubular defects may be creative but cannot replace the specific hollow and tubular architecture of the mucosa-lined trachea required for appropriate function withstanding the respiratory forces and often end up with a permanent tracheostome.12 An allogeneic donor trachea supplies the required mucosa-lined fibrocartilaginous framework. Though, unlike other solid or composite organ transplants, the trachea only has an intrinsic segmental blood supply with vessels, which are too small to allow for direct microvascular transfer. Moreover, the fibrocartilaginous framework may elicit a low immunologic response, but the inner mucosal lining is destined for immunologic reaction since it is its duty protecting the inner tissues from the toxic elements in air that insufflates the windpipe. 2,8 Therefore, we use a preliminary prefabrication step to vascularize an allogeneic windpipe in a heterotopic position under temporary immunosuppression. Journal of Reconstructive Microsurgery
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Hemilaryngectomy for Unilateral Cancer of the Larynx Accepted treatment modalities for laryngeal cancer are radio(chemo)therapy and surgery. Even a unilateral advanced tumor on one vocal fold is usually treated with a total laryngectomy since the reconstruction of a hemilarynx to spare one vocal cord is considered to be very complex.13 However, every attempt should be made to avoid total laryngectomy since the loss of speech and the need of a permanent tracheostoma dramatically change the quality of life of those patients. The technique for extended hemilaryngectomy is designed to allow for functional treatment of lateralized glottic cancer with subglottic extension (T2, T3) and for lateralized chondrosarcomas of the cricoid cartilage. The aim of the reconstruction is to restore the extended hemilaryngectomy defect and to obtain morphology after reconstruction that is comparable to the vocal fold paralysis in the paramedian position.14 Because of its proximity to the larynx, the fibrocartilaginous structure of the trachea and its inner mucosal lining represent excellent donor tissue. For a one-stage reconstruction by simple upward advancement of 4 cm of trachea, a dissection from the surrounding tissues over approximately 8 cm is necessary. Consequently, this segment will have its extrinsic blood supply interrupted. Vascularity will further diminish after modification of the upper 4 cm of membranous trachea to create the convex patch and by placement of a temporary tracheostomy at the anterior wall. Even in nonirradiated cases, advancement of such a large tracheal segment would inevitably lead to patch necrosis. Therefore, we use an orthotopic prefabrication step to vascularize a segment of four tracheal rings.
Methods and Results Orthotopic Prelamination for Short Segment Stenosis of the Trachea To treat short segment stenosis of the trachea, we previously employed a two-stage prefabrication strategy, using the radial forearm fascia as a vascular carrier.7 An H-shaped incision in the forearm is made and the skin is dissected medially and laterally to expose the radial pedicle. The auricular cartilage was sutured on the radial forearm fascia (►Fig. 1). Because of the intrinsic thickness of the cartilage patch, a prefabrication step in situ is required to vascularize the patch before orthotopic transfer 2 weeks later. Once revascularized and transferred into the tracheal defect, mucosa will migrate over the perichondrium of the cartilage patch if we are dealing with a short segment defect. Our actual protocol consists of a 1-step orthotopic prelamination procedure. Thin buccal mucosa is sutured onto the radial forearm fascia (►Fig. 2). After microvascular transfer of the construct to the tracheal defect, a soft stent is inserted to provide for adequate rigidity. After 4 months, the inner mucosal lining is restored and the stent can be removed, leaving a stable tracheal lumen (►Figs. 3, 4).
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Fig. 1 Two-stage prefabrication procedure for short segment tracheal stenosis. (A) A radial forearm fascia flap is procured and used as a vascular carrier. (B) Auricular cartilage is sutured on the radial forearm fascia. The skin is closed on top. After the 2-week prefabrication step to vascularize the cartilage grafts, the orthotopic transfer to the trachea defect is performed. The distal skin monitor flap is sutured in the neck after closure.
Heterotopic Prefabrication of a Tracheal Allotransplant for Long Segment Stenosis of the Trachea A tracheal segment of a human donor (►Fig. 5) is sutured onto the forearm and wrapped with radial forearm fascia overlying the radial vascular pedicle.2 The posterior membranous trachea is resected, creating a horseshoe-shaped construct that can be monitored easily on the forearm. Triple immunosuppression is started following earlier established protocol.2 On a weekly base, the dressing is opened, the trachea cleaned and vascularity of the inner mucosa monitored. After stabilization of the graft, buccal mucosal patches of the recipient are used to replace donor epithelial lining, creating a chimeric mucosal lining of donor and recipient cells. Aim is to gradually replace the allogeneic inner lining, which is prone to immunologic rejection. After 3 months, the long stenotic tracheal segment is resected and orthotopic transfer of the prefabricated donor trachea takes place. Microvascular anastomosis is performed on the neck vessels. A temporary tracheostoma is used and removed once the patient is stable. Immunosuppression is given for 12 months. Tapering starts after bronchoscopic and histologic controls. Once inner mucosal lining and viability of the construct are concealed, immunotherapy is stopped.15 Ventilation perfusion scan, bronchoscopy and computed tomography (CT) scans are used to assess functional outcome.
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Fig. 2 One-stage prelamination procedure for short segment tracheal stenosis. (A) Thin buccal mucosa is sutured on the radial forearm fascia flap, which serves as the vascular carrier. (B) The prelaminated flap is sutured into the defect on the trachea, with the mucosa patch facing inward in an intraluminal position. A temporary laryngeal stent will prevent recollapse during the healing phase.
Orthotopic Prefabrication of Trachea for the Reconstruction of Hemilaryngectomy Defects For T3 glottic cancer, an extended hemilaryngectomy is performed. The tumor is resected with inclusion of the anterior commissure and half of the cricoid cartilage (►Figs. 6, 7). The ipsilateral thyroid lobe and tracheoesophageal lymph nodes are removed as well as the lymph nodes at level II, III and IV of the neck. Only tumors without extension to the supraglottic area are included in this protocol.16,17 Subsequently a radial forearm flap, with a proximal fasciocutaneous and a distal fascial component, is procured (►Fig. 6A to C). The fascial paddle is wrapped around the upper 4 cm of cervical trachea. Two sutures, placed at the lateral side of the defect between epiglottis and aryepiglottic fold, bring the aryepiglottic fold in a midline position posteriorly. The fasciocutaneous paddle is used to temporarily close the extended hemilaryngectomy defect. After microsurgical anastomosis of the radial vascular pedicle to the neck vessels, the flap and the pedicle are covered with an polytetrafluoroethylene (ePTFE) membrane to prevent adhesion formation. An inferolateral corner of the fasciocutaneous segment is Journal of Reconstructive Microsurgery
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Trachea and Larynx Reconstruction with Prefabrication
Trachea and Larynx Reconstruction with Prefabrication
Vranckx et al. modeled and transferred upward into the laryngeal defect. During the second stage, the microvascular pedicle of the radial forearm flap remains intact (►Fig. 7 A to C). After the first operation, the radial forearm fasciocutaneous flap restores the sphincter function of the larynx. Swallowing of solids and liquids is possible after 1 week and speaking is possible during finger occlusion of the temporary tracheostomy. After the second operation, the tracheal patch and the vascularized forearm flap succeed in restoration of the sphincteric and respiratory function. Hand-free speech is possible after closure of the tracheostoma 6 weeks after definitive reconstruction. Voice sounds natural and moderately hoarse.
Discussion
Fig. 3 Drawing of the reconstruction of the trachea defect with a prelaminated radial forearm flap with buccal mucosa. (A) Sagittal view of the reconstructed area: The prelaminated flap with buccal mucosa restores the inner mucosal lining. (B) Axial view: The temporary silicone stent is visible in the center. The vascularized patch of radial forearm fascia and buccal mucosa graft covers the defect. After 3 months the stent is removed. By then the inner mucosal lining has been restored. The loss of airway lumen after stent removal is minimal in limited defects.
The term flap prefabrication was introduced by Yao in the early 1980s19 but the principle of neovascularization by using a vascular carrier to generate a new axial blood supply in tissues goes back to the 1930s.20 Prelamination was defined by Pribaz and Guo21 in 1994 and refers to the process of bonding of distinctive layers, creating a novel anatomic threedimensional laminated structure, without interfering with the native axial blood supply.22 Both prefabrication and prelamination alter the existing anatomical features of tissues and can be considered as a form of “in situ tissue engineering.” Both strategies are used in difficult reconstructions where conventional methods are not available,23 such as for the reconstruction of complex defects of trachea and larynx.
Reconstruction of Tracheal Defects Reconstruction of Short Segment Stenosis of the Trachea
sutured onto the skin of the neck as microsurgical monitoring flap (►Fig. 6 D to 6). After 4 months a second look at the section margins is performed. If histology confirms absence of tumor recurrence, the definitive reconstruction is initiated.18 The ePTFE membrane is removed and the skin paddle is deepithelialized to serve as posterior bulk. The fascia-enwrapped segment of revascularized trachea is isolated, re-
Segmental tracheal resection with end-to-end anastomosis is the treatment of choice for a stenosis encompassing less than 50% of the tracheal length.1 However, traction or tension on the proximal and distal tracheal segment may lead to local necrosis, leakage and fistulization. Scarring due to previous interventions may limit a tensionless closure.3,6 Augmentation of the tracheal lumen by inserting locoregional or distant tissue is necessary when primary closure is not possible, as in
Fig. 4 Computed tomography scans of restenosis and tracheoplasty. (A) Scan at the stenotic site. (B) View after reconstruction with the mucosa prelaminated radial forearm free flap. The silicone stent is visible. (C) CT scan after removal of the silicone stent. Journal of Reconstructive Microsurgery
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preferred tissue combination for the treatment of an airway stenosis in which segmental resection and primary closure is impossible.7
Fig. 5 (A) A donor trachea has been prefabricated on the radial forearm, wrapped in forearm fascia overlying the radial vascular pedicle. A patch of ePTFE protects the allograft. (B) Overview of the tracheal allotransplantation procedure. A donor trachea is wrapped by radial forearm fascia in the forearm in heterotopic position. Buccal recipient mucosa replaces the posterior membrane and patches of allogeneic respiratory epithelium of the donor trachea. After prefabrication the vascularized trachea is transferred to the neck orthotopically. Immunosuppression is stopped when the trachea is in place and bronchoscopy shows well vascularized inner mucosal lining within the tracheal allogeneic framework.
cases of restenosis after previous resection.5 The most frequently harvested reconstructive tissues include cartilage grafts, pericardium and muscle flaps, used as a carrier for skin, periosteum, or bone.4 Since these donor tissues all lack one or more features for optimal tracheal repair, a stable outcome cannot be warranted. Our first protocol was based on an auricular cartilage framework. Whereas bare cartilage undergoes avascular necrosis when directly exposed to the airway lumen,6 we obtained a vascularized construct by means of prefabrication.7 The cartilage is sutured onto a vascularized fascial layer, such as the radial forearm fascia with its intrinsic blood supply. After 2 weeks, ingrowth of blood vessels is complete and the orthotopic transfer can be performed. More recently, we use a one-stage prelamination strategy with a mucosal patch with similar size as the defect, in combination with a temporary silicone stent for 4 to 6 weeks that will prevent prolapse of the mucosa-lined fascia and collapse of the incised and expanded airway.7 The mucosal lining prevents the crusting and desquamation seen when using skin grafts. There is a minor loss in curvature using this one-stage mucosa laminated strategy but without clinical impact if the defect is less than 40% of the tubular curvature. Mucosa-lined fascia, therefore, is currently the
To treat long airway defects, we need more structural support than provided by a prelaminated flap. However, there are no autologous donor tissues available to restore the mucosalined elastic cartilaginous framework. An avascular tissueengineered trachea without inner mucosal lining would be unsuitable for use. The bare tube would be exposed to the airway lumen and to continuous movements during respiration, swallowing, and coughing, preventing ingrowth of the surrounding tissue. Without intrinsic vascularization, scar tissue will be generated.9 Transplantation of an allogeneic trachea brings the required mucosa-lined fibrocartilaginous framework. However, although the vascular requirements of the cartilaginous framework are low and cartilage elicits a limited immunologic rejection, the inner mucosal lining needs a significant vascular supply and its immunologic response is as strong as for regular skin. Since the segmental blood supply to the trachea makes it unsuitable for direct revascularization, most previous attempts at tracheal transplantation have been performed after indirect revascularization, which also avoids the exposure to the bacteria-colonized air. Rose et al reported the first allogeneic tracheal transplantation in a human.10 The donor trachea was implanted heterotopically in the sternocleidomastoid muscle of the recipient and was transferred to the orthotopic position 3 weeks later. The recipient received no immunosuppressive therapy and the report did not document the viability of the allograft or the long-term outcome. Klepetko et al wrapped a tracheal allograft in the omentum of a patient who received a lung transplant from the same donor. Its viability was documented after 60 days of heterotopic revascularization.24 Indirect revascularization of a donor trachea with recipient tissue perfused by a well-defined vascular pedicle is perfectly feasible, as demonstrated by successful outcome in laboratory animals and humans.8,25 After initial prefabrication, a microvascular transfer of the construct can be performed.14 We reconstructed a long-segment tracheal defect in a patient by using an allograft that was revascularized in first stage by heterotopic wrapping in radial forearm fascia.2 Immunosuppressive therapy was necessary during the prefabrication step for establishing connections between the donor’s capillary network around the trachea and the recipient’s fascial blood vessels. This occurred quickly enough to maintain viability of the cartilaginous trachea. However, unlike in the animal model,8 the posterior membranous trachea underwent avascular necrosis. The necrotic segments were debrided and replaced with buccal mucosa. The recipient buccal mucosa grew progressively over the lumen of the cartilaginous tracheal transplant, creating a chimeric patchwork of donor epithelium and recipient buccal mucosa, as visualized by fluorescent in situ hybridization (FISH). Endothelial and respiratory cells originating from the donor disappeared shortly after withdrawal of immunosuppressive therapy. The immunologic rejection occurred silently because of the Journal of Reconstructive Microsurgery
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Reconstruction of Long Segment Stenosis of the Trachea
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Fig. 6 Stage 1: (A) The resection specimen after hemilaryngectomy. (B) The hemilaryngectomy defect preoperatively. In white the ePTFE patch that will cover the fascia flap and vascular pedicle of the prefabricated trachea segment. The tracheal tube assures controlled preoperative respiration. (C) Drawing of the hemilaryngectomy defect. In white the tracheal segment that will be wrapped and prefabricated with the vascularized F. (D) Harvest of the FC and F radial forearm free flap. (E) The FC segment is used to temporarily close the hemilarynx defect and the F segment to wrap and prefabricate the trachea. A microvascular anastomosis is performed on the neck vessels. Usually we perform an end-to-end arterial anastomosis on the inferior thyroid artery and an end-to-side anastomosis on the internal jugular vein; (F) in white the area of resection. The white dots indicate the closure of the aryepiglottic area to recreate the sphincter. (G) and (H) Situation at the end of the first stage. Mark the monitor triangle at the inferolateral FC border and the ePTFE sheet that covers the fascia flap to avoid adhesions in preparation for the second stage. F, fascia; FC, fasciocutaneous.
repopulation of the donor tissue by the recipient’s surrounding vascular network and buccal mucosal cells. The viability of the tracheal cartilage was maintained after all immunosuppressive drugs had been discontinued. There is a meticulous balance between the speed of formation of neovascular connections and the oxygen requirements of the allogeneic Journal of Reconstructive Microsurgery
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trachea. The oxygen requirements of the mucosal lining are high.15 So far, five patients have been treated with seven allogeneic tracheal transplants with variable outcomes.15 Limiting factors remain the speed of revascularization of the inner mucosal lining of the tracheal transplant and the duration of the immunosuppressive therapy. If considering an
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Fig. 7 Stage 2: (A) The prefabricated trachea is opened horseshoe-shaped and remodeled to match the hemilaryngeal defect. The initial fasciocutaneous segment is de-epithelialized and serves as posterior bulk. In white the ePTFE sheet. (B) The hemilarynx defect is restored with the prefabricated trachea segment. In all these steps the microvascular pedicle of the microanastomosis of the first stage remains intact. (C) A combination of radial forearm skin and tracheal autotransplant gives a reconstruction against the midline posteriorly at the level of the vocal fold, while a small convexity is provided anteriorly by the tracheal autotransplant.
allogeneic tracheal protocol for low grade oncologic resections, the duration of immunosuppression becomes even more essential. Further studies should indicate which strategies are useful to enhance the neovascularization process in a clinical setting. We currently investigate the impact of blood originated endothelial cells (BOECs)—to enhance and accelerate the vascularization process of the inner mucosal lining.26,27 The BOECs can be procured from an autologous intravenous blood sample. Cell cultivation of autologous ciliated epithelium may also facilitate the quality and speed of re-epithelialization. Gentle decellularization protocols may retrieve more allogeneic epitopes while leaving the structural support of a donor trachea intact. We believe that a progressive integration of tissue engineering principles into the prefabrication allogeneic trachea model represents the future of trachea and larynx repair.
Reconstruction of the Hemilarynx After hemilaryngectomy for a unilateral larynx cancer, Zur and Urken transferred the trachea pedicled on the thyroid artery and vein with the adjacent thyroid gland in a single stage.28 However, there is an inherent risk of occult metastases to the thyroid gland and the paratracheal lymph nodes, which are commonly seen when there is significant subglottic extension. Therefore, to generate a revascularized autologous tracheal segment, a two-stage prefabrication procedure is required. We reported a modification of the operative sequence compared with our initial procedure. In the first series of patients, we performed the prefabrication of a four-ring tracheal segment by wrapping it with a radial forearm fascia flap.16,18 The prefabrication step took 2 weeks. In a second stage the tumor was resected and the hemilarynx was restored with the prefabricated tracheal construct. However, the prefabrication step in the first stage, before tumor resection in the second stage, could manipulate tumor cells and elicit spreading. The conversion of sequence, however, proved to be difficult: When the tumor is resected primarily, a hemilaryngeal defect exists at the time prefabrication of the trachea has only started.17,18 The hemilaryngeal defect, therefore, needs to be temporarily closed to allow breathing
and swallowing, while the prefabrication step takes place. Experience after reconstruction of 25 cases allowed us to modify the prefabrication sequence leading to optimal functional results without impairing oncological safety (n ¼ 65). Swallowing function recovers within a week after the first and second intervention, and the laryngeal respiratory function is fully regained after closure of the tracheostomy.17,18 Tracheal autotransplantation leads to optimal reconstruction of extended hemilaryngectomy defects.
Conclusion Orthotopic and heterotopic prelamination and prefabrication strategies offer innovative, efficient and reproducible solutions for the restoration of challenging short and long segment tracheal defects, as well as of unilateral laryngeal defects, previously considered almost inoperable. Gradually cell and tissue engineering strategies will be implemented to improve neovascularization and matrix formation and to introduce more autologous cultivated elements in context of allogeneic trachea transplantation.
Disclosure The authors have no commercial associations or financial disclosures to make. Margot Den Hondt has a scientific fund of the FWO Fonds Wetenschappelijk Onderzoek Vlaanderen. Presented in part at the American Society of Reconstructive Microsrugery, Naples 2013 and at the World Society of Reconstructive Microsurgery, Chicago 2013.
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