Preclinical and human tracheal replacement with aortic grafts: a narrative review

Introduction

Background

Following the seminal articles by Belsey (1) and Grillo (2), numerous reviews have been published in the field of tracheal replacement (3-21). However, most do not differentiate between patch tracheal reconstruction (PTR), C-shaped/non-circumferential tracheal replacement (NCTR), i.e., sparing the tracheal membrane and its vasculature, and full-circumferential tracheal replacement (FCTR). This distinction is essential in terms of postoperative mortality. Furthermore, one recent study mixes both tracheal and bronchial reconstruction rendering the results confusing (20). Finally, only two studies and one editorial are focused on FCTR, which constitutes the major challenge in the field (16,19,21). So far, the most widely used tracheal substitutes are the cartilage-reinforced forearm free flap (FFF) and the cryopreserved aortic allograft (CAA), respectively (21). The latter is the simplest option. It does not require any immunosuppressive drugs and resists active infection.

Objective

The aim of our study is to identify and report results of both preclinical and human use of the aortic grafts in tracheal replacement with a focus on the benefit/risk assessment in clinical practice. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-55/rc).

Methods

For the purpose of a PhD thesis of one of us (A.W.) entitled “Extended replacement of the trachea: clinical and experimental studies” defended in 2014 at the University of Lille, France (available at https://theses.fr/2014LIL2S007), we had already performed an in-depth literature search (PubMed: National Center for Biotechnology Information, U.S. National Library of Medicine, Bethesda, MD, USA) in order to identify articles related to tracheal replacement. Additional articles were identified in a similar way (PubMed/MEDLINE) up to September 2025 and from the bibliography of relevant publications. Finally, articles focused on experimental and human use of aortic grafts for tracheal replacement, including the authors’ experience, were reported in a narrative fashion. In the field of human use, patients reported in multiple publications were included only once. Additionally, supplementary data were provided through electronic communication with several authors. Methods are summarized in Table 1.

Study identification and discussion

In the setting of preclinical studies and following both seminal articles from Pressman and Simon published in 1958 and 1959 (22,23), we identified 20 additional articles up to 2025 (24-43) and one relevant abstract (44). In the field of human tracheal replacement with aortic grafts, we retrieved 20 articles from 1999 to 2025 (45-64). The aortic substitute was first used in pediatrics in the form of PTR (45,46). In adults, we notably reported the world-first case series of FCTRs by means of aortic allograft between 2005 and 2007 (49,50).

Preclinical studies

In the setting of preclinical studies, the animal models were sheep (n=7), rabbit (n= 6), dog (n=3), pig (n=3), and rat (n=1). In 1958–1959, Pressman and Simon performed FCTR up to 10 tracheal rings in length on more than 120 dogs at the cervical level by using a lyophilized aortic allograft (LAA) supported by a polyethylene tube stenting. The graft was revascularized by muscular surroundings of the cervical trachea. From a structural viewpoint, LAA transformed into a fibrous pseudotrachea, with ultimate epithelialization of the luminal surface. This pseudotrachea remained a flaccid conduit with consecutive respiratory collapse, thus requiring permanent polyethylene tube stenting. Second, over the months, the LAA was subject to contraction leading to elongation of the remaining trachea with adjacent rings distorted in shape, particularly in cross-section. This elongation could offer the possibility of delayed tracheal end-to-end suture. The third phenomenon was metaplasia of rings from cartilage to bone at the level of the severed ends of the trachea. Finally, the authors concluded: “From the practical standpoint, no homograft created from any other structure or any artificial implant has been found to be of equal value to the use of aorta in the repair of large tracheal defects.” (22,23).

In the late 1990s, Carbognani et al. conducted a study in two phases in a New Zealand (NZ) rabbit model. First, a CAA segment was wrapped with the omentum in 10 animals. Second, a similar omental flap-wrapped silicone-stented CAA was transplanted into the trachea in another group of 10 animals. Sacrifices were scheduled on days 7, 14, and 21. In phase one, angiogenesis was present on day 7 with no signs of immune rejection, and after day 14, intense fibroblastic proliferation invaded the lumen of the CAA. In phase two, eight rabbits survived, in which similar findings were shown, save that the fibroblastic proliferation was restrained by the endoluminal stent (24,25).

In 1999, Feito et al. studied a composite graft constructed with a fresh aortic allograft (FAA) or a CAA surrounded by a polytetrafluoroethylene (PTFE) prosthesis in a rabbit model. Thirty-eight animals underwent a 1-cm cervical FCTR and were followed for up to 4 months. Of 38 animals, 35 survived. Microscopic examination showed a partial or total necrosis of the graft wall, which was not surprising since the PTFE prosthesis impeded graft angiogenesis from the surrounding tissues (26).

From 2001 to 2005, Martinod et al. contributed significantly to the field (27-29). They demonstrated in sheep models that tracheal reconstruction using an aortic autograft (27,28), and then an FAA (29) could result in the formation of mature tracheal tissue, in particular cartilage rings stiff enough to allow the removal of the stent temporarily placed to prevent collapse of the transplanted aorta. This occurred without rejection, in the absence of any immunosuppressive drugs. FCTR by means of FAA performed with a gender mismatch between the donor and the host seemed to demonstrate that the newly formed cartilage originated from cells of the host, and that epithelial regeneration resulted from a cell migration from the edges of the native trachea anastomosed to the graft (29). These results were reproduced by Seguin et al. (Martinod’s group) on the same animal model, after replacement of the carina (30), and finally with CAA, while decellularized aortic allografts and glutaraldehyde-treated aortic grafts failed to achieve satisfactory substitutes (31). To assess whether these results were reproducible in another mammal, similar investigations were conducted in a mini pig model. These were considered as a prerequisite for the first implementation of this technique in humans (49). Thirty-seven animals underwent surgery involving long cervical (n=17) or thoracic (n=20) FCTR, using FAA (n=21) or CAA (n=16) (32,33). Important findings were discovered. First, the need for stable stenting, preferably with a Y-shaped silicone stent to prevent dislocation. Second, the presence of distorted cartilage rings close to the aortic graft or its transformation in an hourglass-shaped stenosis, critical (n=6) or asymptomatic (n=4), following the stent removal at 12 months (Figure 1). This latter finding meaning prolonged stenting is potentially necessary for a human use. Third, the value of CAA, for reasons of immune tolerance, bacteriological and virological safety, and availability.

Figure 1 Macroscopic view of a specimen 13 months after full-circumferential replacement of the trachea with a 10-cm long cryopreserved allogenic aorta, from the thoracic inlet down to the main carina, in a minipig. One month after stent removal, a major 2-cm long hourglass-shaped stenosis of the grafted area is shown above the carina (star). The overlying tracheal segment shares 19 native cartilage rings.

However, de Delva et al. (44) and Tsukada et al. (34) using FAAs in sheep models, with a methodology similar to that previously described (29,32), failed to replicate the results of French teams, casting doubt on the concept of tracheal regeneration. Notably, among their group of 10 animals, Tsukada et al. showed a high rate of inadvertent death or euthanasia (60%). The FAAs “eventually became necrotic, slough, and were expectorated, aspirated, or swallowed”; and at best, transformed into an hourglass-shaped stenosis in the four animals that survived long enough (Figure 2) (34).

Figure 2 Macroscopic view of a specimen 6 months after replacement of the cervical trachea with an 8-cm long FAA in a sheep. Grafted area length was 1.5 cm in diameter. No evidence of neocartilage formation between proximal and distal native tracheal cartilage rings. Adapted from (34). FAA, fresh aortic allograft.

Aside from both landmark studies (22,23), two additional experiments were conducted in the dog model. The former was PTR using an aortic autograft after window resection of the anterior tracheal wall (36). The latter was the use of either FAA or CAA for FCTR (37). In both studies, pathological examination revealed regeneration of the tracheal epithelium and angiogenesis of the grafted aorta. Furthermore, after the second experiment (FCTR), sparse islands of nascent cartilage were shown within the aortic graft, which transformed into mature cartilage at 12 months. Graft contraction up to 68% was also shown as previously described (22,23,34,35). The authors concluded that the cartilage, in the absence of ring-shaped structure, did not allow the tissue to function as native trachea.

In 2012, in the NZ rabbit model, we developed the construction of a tube-shaped tracheal substitute with either FAA or CAA wrapped in a lateral-thoracic fascial flap and implanted under the skin of thoracic wall (38), as previously described by Delaere et al. (65). This construct was well vascularized with no evidence of graft rejection. In three animals implanted with gender mismatch, the fluorescence in situ hybridization (FISH) analysis for detection of X and Y chromosomes demonstrated the migration into the graft of recipient’s cells coexisting with donor’s viable smooth cells (Figure 3). This finding was suggestive of moderate ischemia during the initial phase of angiogenesis. However, our construct was not stiff enough to be suitable for FCTR. Therefore, it was only investigated for esophageal replacement in a rabbit model (66). To solve the issue of the flaccidity of the construct, we conducted two phases of additional investigations of a composite graft mimicking a native trachea in NZ rabbits (39). FAAs or CAAs, with an external allogenic cartilage-ring support (5-to-7 rings), were wrapped in a lateral-thoracic fascial flap as previously used (38). The first group of nine animals undergoing implantation of the construct under the skin of the chest wall was found to have a satisfactory stiffness and preserved histological structure of cartilages, while moderate to severe aortic ischemic lesions were seen. In the group of 10 rabbits having undergone a staged FCTR (7-to-9 day of heterotopic fascial revascularization of the construct under the skin, followed by transposition to the neck for FCTR, after 8-to-10 tracheal-ring resection), the anatomical results were characterized by the discrepancy between the severity of ischemic lesions involving both aortic graft and cartilage rings, and the satisfactory biomechanical profile of the construct in seven of 10 animals. This was probably due to allogenic-cartilage calcification deposits ensuring stiffness. Thus, mixed pathological findings did not allow a potential use of a similar construct for human needs.

Figure 3 FISH analysis (magnification of 200×) of a female rabbit aortic allograft with its autofluorescent elastic fibers, showing migration of cells from the male rabbit recipient with both X (red fluorescence) and Y (green fluorescence) labeled chromosomes. Persistence of normal XX-labeled smooth cells of female origin (double-red fluorescence). FISH, fluorescence in situ hybridization.

In 2013, Seguin et al. (Martinod’s group), by using FAA in an NZ rabbit model, studied the role of mesenchymal stem cells (MSCs) in the possible process of tracheal regeneration into the aortic graft. They elegantly demonstrated the migration of MSCs within the grafted area by marking them through transfection with a fluorescent protein detected by in situ hybridization (40). With a maximum 18-month follow-up, rabbits showed well-integrated and thickened FAA. Graft contraction up to 40% was also shown. However, there were no arguments for tracheal remodeling, since no organized cartilage was observed. Only islands of nascent cartilage were present in close proximity to anastomoses. Therefore, the morphological description of the grafted area did not support tracheal regeneration.

In 2023, the study conducted by Tsou et al. in a pig model demonstrated the failure of decellularized aortic allograft for FCTR (41), in line with the previous investigation conducted in a sheep model (31).

In 2024, Wei et al. (42) evaluated the use of polyvinyl-chloride-stented FAA for FCTR in a Wistar rat model. Transplantations were performed with gender mismatch. The FAAs became necrotic at the initial phase, as shown in Fig. 3A of their article. Despite this drawback, successful epithelial and cartilage regeneration and seamless anastomosis integration were observed within 6 months. Additionally, in situ hybridization seemed to demonstrate that cartilage regeneration originated from male recipient’s cells.

Finally, in 2025, Hung et al. conducted in a rabbit model a relevant study. After reconstruction of 5 mm × 5 mm tracheal defects with CAAs, they demonstrated that chondroprogenitors from adjacent tracheal perichondrium were critical for neochondrogenesis within the grafted area (43).

Procedures, outcomes, gross morphology, pathology, and key points of preclinical studies are summarized in Tables 2-4.

Human tracheal replacement with aortic grafts

The human application of an aortic graft in tracheal surgery started in the late 1990s in pediatrics. In the case series of Chahine et al., patient #3 was a 1-year-old infant who underwent a 1.5-cm diameter PTR with a CAA for the treatment of a tracheoesophageal fistula about 2.5 cm above the carina, while the longitudinal defect in the esophagus was closed in a single layer. An intercostal muscle flap buttressed the two repairs. The recovery was uneventful, and 1 month later the patch was covered with epithelium (45).

In 2004, Hazekamp and Nijdam performed a tracheoplasty for long-segment tracheal stenosis in a neonate, by using an autologous patch from the ascending aorta, after division of one arch of a tight double aortic arch. This patient remained asymptomatic 12 months after PTR (46).

In adults, the aortic graft was used first in an emergency setting. Facing a complete tracheal anastomotic disruption in a context of graft dysfunction after heart-lung transplantation, Hoffman et al. interposed a 22-mm CAA to bridge the tracheal defect before heart-lung retransplantation, which, fortunately, was carried out 3 days later. At the last follow-up, the patient had good graft function and normal exercise tolerance (47).

The first case of FCTR with an aortic autograft was reported by Azorin et al. in 2006, for the treatment of a squamous cell carcinoma of the upper trachea (48). A 7-cm segment was harvested from the infrarenal abdominal aorta and was replaced by a Dacron tube. After resection of the lesion, the aortic autograft, supported by a silicon stent, replaced the tracheal defect. The survival was 6 months. According to CT scan examination showing a circumferential tumor in close contact to the cricoid cartilage, and finally a positive proximal tracheal margin, it appears to us that a laryngotracheal resection, followed by the construction of a mediastinal stoma, could have been considered in this case.

Our personal first-in-human experience of FCTR with aortic allografts from 2005 to 2007 (Wurtz’s group) was reported in two steps (49,50). First, two patients suffering from mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) of the trachea, respectively, were operated in a compassionate setting, by means of an FAA harvested from a brain-dead donor (49). Second, four additional patients were included in a prospective research program entitled “Tracheal replacement with cryopreserved aortic graft”, which was approved by the French Bioethics Advisory Board, the French Agency for Health Safety (AFSSAPS), and our institutional review board (50). They all underwent an FCTR for ACC, with no postoperative mortality, despite additional resection/restitution of the carina in three of them. However, in the post-operative period, among the group of six patients, three sustained life-threatening adverse events, notably acute respiratory distress syndrome rendering this procedure questionable (67). Demographics of patients, diagnosis, procedures, R0/R1 status of resection, outcomes, and current status up to 216 months are summarized in Table 5. All clinical procedures described in this study were performed in accordance with the ethical standards of our national research committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from patient #6 (Table 5) for the publication of this article and accompanying images.

In 2007, Brian et al. reported an extended surgery for metastatic tracheobronchial melanoma (51). An FCTR with carinal restitution was performed, using an aortic autograft surrounded by a metallic spiral support. Follow-up bronchoscopy showed the progressive expectoration of the necrotic graft, replaced by a well-vascularized granulation tissue encompassing the metallic support. Unfortunately, this patient died from massive pulmonary embolism 5 weeks later.

In the emergency setting, two cases of tracheal dehiscence after tracheal resection and primary anastomosis, treated by interposition of CAA, were reported by Davidson et al. in 2009 (52) and Zanetta et al. in 2014 (53), respectively. The first patient, having undergone a 4.5-cm resection of the trachea for a tracheoesophageal fistula, received a 6-cm CAA supported by a Montgomery T-tube for the correction of an anastomosis dehiscence. Unfortunately, he died from generalized mediastinitis secondary to recurrent dehiscence, probably due to the absence of wrap (68). The second patient was a 4-year-old pediatric female having undergone a cricotracheal resection (CriTR) and primary anastomosis for postintubation stenosis. On day 8, she experienced partial dehiscence with the impossibility to perform an end-to-end reanastomosis. The defect was reconstructed by a 10-cm CAA, wrapped by a thymopericardial-fat flap (69), and supported by a Montgomery T-tube. Even though the CAA transformed into a well-vascularized conduit, neither calcification nor stiffness were shown in the long term, and the patient was not decannulated 10 years later (information obtained through electronic communication with the authors in December 2022).

A relevant article was published in 2016. Comparison is made between PTR, using either CAA (n=5) or acellular dermal matrix (n=3) buttressed with muscle flap or epiploon, for the correction of bronchial (n=2) or tracheal defects (n=6). Both materials provided similar results in term of airtight closure and mid-term outcomes (54).

The significant clinical experience of Martinod’s group, which started in October 2010, was reported in five articles (55-59), including a registry: the TRITON-01 study (57). Unfortunately, the case mix of bronchial and tracheal replacement, miscellaneous indications not related to tracheal surgery, and sometimes discrepancies of data for the same patient reported in different articles, led to some difficulties for interpretation and synthesis in our review. Nevertheless, we were able to pool the more relevant data and findings of patients, in which various types of tracheal replacement with FAA or CAA were performed, from October 2010 to October 2023 (n=31). The main surgical indication was advanced thyroid or parathyroid cancer invading the trachea (n=12), tracheal ACC (n=11), postintubation tracheal stenosis (n=5), and other types of tracheal tumor (n=3). Concerning the postoperative course, the overall mortality rate within 90-day was 13% (4/31), with an increased risk factor in cases of FCTR, leading to a mortality rate of 23.5% (4/17). Demographics of patients, diagnosis, type of resection, lengths and location (according to author’s topographic classification in types I–III), R0/R1 status of resection, outcomes, and final patient status are summarized in Table 6.

Following coronavirus disease 2019 (COVID-19) infection, extensive damage to the trachea was observed, mainly in patients who survived after mechanical ventilation. In this context, an Italian team reported an original technique of FCTR, extended up to the cricoid cartilage down to the carina, by means of a CAA wrapped with the great omentum. The membranous portion of the trachea was preserved, and its mucosa was cauterized, thus creating an effective interposition between the esophagus and the silicone-stented-wrapped graft. The patient experienced a favorable outcome with a 2-month follow-up (60). Afterwards, five additional patients underwent a similar procedure. So far, four of them are stent-dependent but in excellent health. Another one, after an uneventful postoperative course, unfortunately, developed a fatal tracheo-innominate artery fistula 3 months after surgery (61).

Two cases of benign tracheal stenosis surgery, followed by adverse events, were reported in 2024. First, a 17-year-old female in poor condition (morbid obesity, psychiatric disease), who presented with postintubation tracheal stenosis, underwent rings 3–7 resection and primary anastomosis. Thirteen days later, she experienced an anastomosis dehiscence. To restore tracheal continuity, a right FFF was harvested but thrombosed prior to vessel ligation, and an attempt to use a deltoid flap also failed. As salvage surgery, an 8-cm CAA supported by a Hood T-tube was implanted to correct the defect, with the graft partially buttressed with a part of the deltoid flap. The patient experienced a favorable outcome 25 months postoperatively (62). Second, a post-tuberculosis stenosis of the lower trachea was treated by a 5-cm FCTR with a CAA supported by an uncovered self-expandable metallic stent. Subsequently, the patient experienced recurrent granuloma formations managed through repeated endoscopic removal. An attempt to remove the stent failed, since the patient developed a stenosis of the graft 15 days later, requiring a redo stenting, and then repeated bronchoscopy for granuloma problems (63).

Finally, a 67-year-old male presented with postintubation stenosis of the cervical trachea, which was treated by a 5-cm FCTR with a silicone-stented CAA. The postoperative course was uneventful. This observation demonstrated the possibility of stent removal after 17 months, and a long free-of-stent period of survival without respiratory support, up to death 5 years and 7 months after surgery (64).

Overall, 58 cases of tracheal replacement with different types of aortic grafts were reported in the world literature for benign (n=24) or malignant (n=34) pathology (Tables 7,8). The in-hospital mortality rate (or within 90 days) was 0 for both PTR/CriTR and NCTR (n=21), and 18.9% in the case of FCTR (7/37).

Preclinical studies: discussion

In the late 1950s, Pressman and Simon provided the main characteristics of allogenic aorta heterotopically implanted in the trachea (22,23): satisfactory immune tolerance, and resistance to endoluminal infection; satisfactory angiogenesis, the trachea being dissected as closely as possible from the well-vascularized surroundings of the cervical area. From a structural viewpoint: (I) as a result of epithelial cells ingrowth arising from the severed ends of the native trachea, the intimal surface was progressively covered by an epithelial lining, at first in the form of squamous metaplastic epithelium, and then as a mucociliary epithelium. An endoluminal tube restrained the concomitant fibroblastic proliferation, originating from the subendothelial conjunctive tissue, and susceptible to impede the epithelialization (24,25). The preservation of the tracheal membrane, with its epithelial lining, accelerates significantly the epithelial coverage. This process is, however, non-specific to heterotopically transplanted aortic grafts. It was described in the early 1950s after tracheal replacement, using another bio-prothesis (70), synthetic non-absorbable substitutes (71-74), bio-absorbable scaffolds (75,76), or after tracheal transplantation in numerous animal models (77-82), notably with an epithelium-denuded tracheal allograft (83). (II) Another important finding was the contraction over time of the aortic segment in a longitudinal direction up to 50/70%, resulting from fibrosis which, additionally, elongated the remaining trachea by widening the membranes between the cartilage rings. This “graft contraction phenomenon” (84) was associated with untoward centripetal shrinking, which was, fortunately, restrained by the use of the polyethylene tube stenting. This phenomenon would be of sufficient magnitude to allow a potential two-staged end-to-end tracheal reconstruction, whereas it was not possible initially (23,34). (III) Over the years, the pseudotrachea remained a flaccid conduit, with no sufficient rigidity to permit inspiration without collapse. Similar findings were shown by others in the pig model: “after three months, grafts consistently showed a thickened, pink, and flaccid aspect resembling an esophagus”. Longitudinal contraction up to 50% was also described in this investigation (33). (IV) Finally, Pressman and Simon pointed out a striking phenomenon, the osseous metaplasia of tracheal rings adjacent to the graft area. After 5 years, these tracheal rings distorted in shape and elongated, and bone formation was completed with the formation of trabeculae. The stiffness of these structures could act as supports to maintain some patency to the shrunken graft.

Later on, Martinod’s group launched additional investigations of both FAA and CAA as tracheal substitutes in the sheep model. Aside from the already well-documented lining of the luminal surface by a respiratory epithelium, they provided additional findings that had never been described before, namely newly-formed cartilage rings into the graft and a posterior membrane. Based on previous description by Pressman and Simon of the fibrosis of aorta and its subsequent contraction (23), Hermes Grillo, in his invited commentary, hypothesized that “new cartilage rings” described in the 2005 article by Martinod et al. (29) were, in fact, previously present marginal tracheal rings “pulled into a vigorously remodeling and contracting connective tissue mass around the intraluminal stent”. This phenomenon could cause both mature cartilage of marginal tracheal rings of the recipient and residual elastic fibers of the aortic graft to appear on the same transverse section on microscopic examination, particularly in the transition zones between the native trachea and the grafted area. Therefore, these findings could be misinterpreted as a “new cartilaginous ring”. Another cause for concern is Fig. 1 of another article by Martinod et al., published in 2003, showing a macroscopic view of a 24-month sheep specimen (28). From our viewpoint, it seems that forceps tips most likely delineate a native tracheal segment with seven cartilage rings of normal morphology rather than “new cartilage rings”, while the shrunken grafted area is shown on the left, close to the left forceps (Figure 4). Indeed, the graft area appearance is similar to that observed by Tsukada et al., who failed to replicate the results of the French team (Figure 2). A similar misinterpretation probably occurred in another article reporting investigations in a pig model, in which Fig. 1 shows a macroscopic view of a specimen 15 months after FCTR with CAA (33). After careful examination, it appears to us that arrows most likely delineate a native tracheal segment, with nine cartilage rings and membrane of normal morphology, rather than “the regenerated trachea”. In fact, the shrunken graft area is located just above the main carina (Figure 5). These findings raise major doubt about the reality of trachea regeneration of aortic grafts used as biologic scaffold (85).

Figure 4 Macroscopic view of a specimen 24 months after full-circumferential replacement of the cervical trachea with an autologous aortic graft in a sheep. From our viewpoint, forceps tips most likely delineate the distal native tracheal segment with seven cartilage rings of normal morphology (similar to those shown at the level of the proximal native segment). The shrunken grafted area is shown close to the left forceps tip, between the proximal native segment sharing five normal rings, and the delineated distal native tracheal segment. Adapted from (28).

Figure 5 Macroscopic view of a specimen 15 months after full-circumferential replacement of the trachea with a cryopreserved allogenic aorta, from the thoracic inlet down to the main carina, in a minipig. From our viewpoint, arrows most likely delineate a segment of the proximal native trachea, with nine cartilage rings and membrane of normal morphology. The shrunken grafted area is shown between “A” (ostium of the left main bronchus) and the right arrow. “B” shows the ostium of the right main bronchus. Adapted from (33).

On the other hand, neochondrogenesis is a well-known process shown in orthotopically implanted CAAs, which calcify over time (86). Thus, it is not surprising that newly-formed cartilage might appear within CAA heterotopically implanted into the trachea. In fact, in a sheep model, de Delva found islands of immature cartilage in two of six animals (44). In a dog model, Kim et al. found sparse islands of immature cartilage around the anastomosis sites, which matured over time, generally at 12 months. They also found numerous cartilage fragments on the center of grafts examined at 16 months, but no ring-like organized cartilages (37). The mechanism leading to neochondrogenesis and calcification within CAA is poorly understood. Mathieu et al. suggested that inflammatory cells, through the expression of transforming growth factor-beta1, induced smooth cells within the aortic graft to transform into cartilage, and then to undergo further endochondral ossification (86). This hypothesis is supported by the fact that viable smooth cells persist within heterotopically implanted CAA, as we demonstrated thanks to the FISH analysis (Figure 3), in our rabbit model (38). The involvement of recipient’s CSMs in this process is another possibility, their migration into the graft area being clearly demonstrated (40). Since the CAA sustains a period of warm ischemia following implantation before neoangiogenesis becomes effective, cartilaginous tissue might be likely a part of tissue scarring of ischemic/damaged organ, in which different types of stem cells migrate and exert their reparative effects at the site of injury (87,88). Recently, Hung et al. hypothesized that newly-formed cartilage originated from recipient perichondrial progenitor cells (43). Finally, the mechanism of cartilage occurrence within the aortic graft might be multifactorial. Main hypotheses are summarized in Table 9.

Human tracheal replacement: discussion

Our bibliographic search retrieved a total of 58 cases of tracheal replacement with aortic grafts, among which were 37 patients included in two prospective research programs. The former (Wurtz’s group) was focused on tracheal and carinal replacement for extended salivary gland-type carcinoma, and in our reports (49,50), we highlighted: (I) the importance of a stable stenting with a Y-shaped silicone stent to prevent dislocation. (II) The importance of effective 360° graft wrap with bulky and well-vascularized flaps, such as the pectoralis major associated to the thymopericardial-fat flap (69), to optimize angiogenesis, and prevent life-threatening events, such as esophageal or vascular erosion (Figure 6A). Later on, thanks to the long follow-up of patients up to 216 months, we were able to confirm the fate of graft, as detailed in preclinical studies by the end of the 1950s (22,23), notably the absence of cartilage remodeling, and the graft contraction up to 60% in the axial direction, allowing the Y-shaped silicone stent to be replaced by a 4–6 cm well-tolerated silicone stent (Figure 6A,6B). From an oncological viewpoint, despite an extended surgery in a curative intent, i.e., macroscopic complete resection and R0 tracheal and radial margins, the results were disappointing, since four patients who survived a long period finally died of metastatic disease, also associated with a local relapse in patient #5. So far, only patient #6, who had sparse lung metastases treated by radiofrequency, and esophageal relapse treated surgically, is still alive at 216 months, with no evidence of disease (NED) (Table 5). Finally, the NED period after FCTR was 3 to 12 years (mean, 7.8 years). According to the life-threatening adverse events shown in three out of six patients, with a risk-benefit ratio judged negative; and, in parallel, the impressive results of chemoradiation with a 100% efficacy for locally advanced ACC of the trachea, reported by Allen et al. in December 2007 (89), we decided to stop the inclusion of additional patients in our prospective clinical trial in the end of 2007 (90,91). This ethical attitude was, retrospectively, supported by two additional reports highlighting the value of chemoradiation for the local control of locally advanced ACC (92,93).

Figure 6 Graft contraction over the years in patient #6 (Table 5). (A) Trachea measuring 130 mm in length. 90-mm FCTR with CAA (90 mm) supported by an 11-cm Y-shaped silicone stent, leaving five native cartilage rings in place. The TPFF, with its ITA blood supply (forceps tips), creates an interposition between the esophagus and the graft. Operative view before interposition of the pectoral muscle flap between the anterior aspect of the graft and large vessels. (B) Chest computed tomographic scan after 8-year follow-up. The length from the vocal cords to the distal trachea is 89.6 mm, demonstrating 55%-length contraction of the graft (blue arrows). The retracted CAA is supported by a 6-cm straight silicone stent. AA, ascending aorta; CAA, cryopreserved aortic allograft; FCTR, full-circumferential tracheal replacement; IA, innominate artery; ITA, internal thoracic artery; TPFF, thymopericardial-fat flap.

In the second series (Martinod’s group) summarized in Table 6 (55-59), the main surgical consideration was advanced thyroid or parathyroid carcinoma invading the trachea (n=12). In this setting, we think it might be relevant to discuss the repair of tracheal defects by using the sternocleidomastoid myoperiostal flap (52 cases in the literature since 2000). It is a relevant technique because the flap is autologous, easy to harvest, and ensures a stable airway without the need for prolonged stenting (median time, 56 days) (94-97). Another subgroup of patients was operated for tracheal ACC (n=11). As in our series, morbidity was high, but there were no in-hospital deaths. The pathological results were impressive for tumors that spread into the submucosa: tracheal margins negative (R0, n=9); positive (R1, n=2). However, in contrast with our series, the average follow-up time of 18 months (range, 1–43 months) was too short to assess the curative value of the procedure, and two R0 patients already had a recurrence, leading to death at 36 months in one of them (Table 6).

Aortic graft and internal stenting

In humans, internal stenting is an essential part of the procedure apart from PTR, where it is used on a case-by-case basis (54). Silicone stents were routinely used. Their intraoperative placement could be performed under bronchoscopic guidance (50,60), rather than through an anterior incision of the graft that might facilitate a delayed rupture with mediastinitis (98). Due to the graft contraction over time, they are chosen shorter with systematic change every 2 years. As a result, they are being increasingly tolerated. Uncovered self-expandable metallic stents should be avoided, because they promote granuloma formation (63). Severe complications are uncommon, such as erosion of great vessels, leading to massive hemoptysis observed in two patients (50,61), stent dislocation or obstruction shown in three patients, notably after carinal restitution (57). Data enabling consideration for definitive stent withdrawal, which was possible with sufficient follow-up in a few number of patients (Table 6), might be: (I) partial replacement (PTR/NCTR) mainly in the cervical area; (II) inferior or equal to 50 mm; and (III) calcification deposits into the graft (64).

Surgical considerations

Tracheal replacement with CAA is useful in an emergency setting, in the case of tracheal anastomosis dehiscence (47,53), or failure of another technique (62). In contrast, due to mixed results (4/6 stent-dependent patients in the long-term), its use is questionable in the treatment of postintubation cricotracheal/tracheal stenosis. In the treatment of advanced thyroid cancers invading the trachea, other more reliable techniques exist (97,99). Given the efficacy of chemoradiation (89,92,93), it appears to us that the benefits do not warrant the risks of FCTR for local control of ACC of the trachea, as we have been stating for a decade (21,90,91,100), an opinion currently shared by a leader in tracheal transplantation (101).

Finally, taking into account the overall in-hospital/90-day mortality rate, we think it is important to highlight the significant difference between partial replacements (PTR/NCTR) and FCTR (19,21). Maintaining the tracheal membrane intact and its vasculature leads to a postoperative mortality rate of 0 in 21 patients vs. 18.9% for FCTR (7/37) (Tables 7,8), and reports that combine the two types of tracheal replacement result in a confusing downward rate revision (20). Physicians must keep in mind the postoperative mortality in the real world when an FCTR is considered, mainly in cancer patients (mortality rate 20%: 5/25) (Table 8).

Strengths and limitations

In comparison with other articles, our world literature review of preclinical and human tracheal replacement with aortic grafts, performed over the years, is close to exhaustive. Indeed, in 2018 Siddiqi et al. (13), in an article focused on the topic, reference only four preclinical studies (33,34,37,40), and identify only nine patients (50,52,55) vs. 20 in our present review (45-55). Similarly, in a recent systematic review focused on all types of tracheobronchial replacement techniques, including the use of aortic grafts (20), five case reports (51,94,102-104), and six important series reporting a total of 89 patients (54,61,95,97,105,106), are lacking, mainly in the field of thyroid cancer invading the trachea.

One drawback of our review is the small number of reported pathological findings in humans. Only four patients were reported with graft biopsy results, showing an internal surface focally lined with mucociliary epithelium. Residual islets of elastic fibers were also shown into a dense inflammatory infiltrate 1 year after transplantation (50). To our knowledge, no deceased patients underwent autopsy for a morphological and pathological study of their transplant. Another limitation is the small number of patients in each subgroup of pathology, which does not allow definitive conclusions to be drawn regarding care and/or the course of action to be taken.

Future research

The main drawback of aortic graft is the need for permanent stenting in the majority of cases. To solve this issue, we launch a preclinical study of a prosthetic bio-integrable tracheal ring to reinforce a recently described tube-shaped thoracic flap based on the internal thoracic blood supply (107), in a sheep model.

Conclusions

The aortic graft has attracted the interest of surgeons for tracheal replacement due to its tubular morphology, close to the tracheal diameter, its low immunogenicity, and its resistance to active infection. From a structural viewpoint, our studies of preclinical and human use of aortic grafts implanted in tracheal heterotopy show that they transform into flaccid tube-shaped scar tissue that contracts over time around the luminal support, up to an average of 60%. Occasionally, the graft is subject to endochondral ossification and can get a certain degree of rigidity, allowing the stent to be removed in human practice. The CAA is particularly useful in the emergency setting, being readily available in tissue banks. Outside of these situations, indications might be discussed on a case-by-case basis, taking into account the risk-benefit ratio and non-surgical treatment options, mainly in the field of low-grade radiosensitive malignancies such as ACC of the trachea.

Acknowledgments

We thank Professor Eric Kipnis and Audrey Wurtz Laurent for editorial assistance.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-55/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-55/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-55/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study were performed in accordance with the ethical standards of our national research committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from patient #6 for the publication of this article and accompanying images.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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