Keywords

Introduction

Most tracheal disorders requiring resection do not affect the entire length of the trachea. Resection of short tracheal segments was first reported mid twentieth century [1, 2]. Subsequent development of mobilization techniques helped to extend the resectable length up to several centimeters [3]. Reconstruction via primary anastomosis to re-establish a patent airway can therefore be performed safely in the majority of patients referred to a thoracic surgeon [4]. However, in rare cases, neoplasms, iatrogenic injury, and autoimmune disease can involve most of or the entire length of the trachea, creating an unmet clinical need for a suitable replacement. Over the past century, scientists and surgeons have tried to meet this need by exploring synthetic tracheal prosthesis, tracheal transplantation, tracheal replacement with biomaterials, tracheal replacement with autologous tissue, and tissue engineered tracheal grafts [5, 6]. This chapter focuses on outcomes of tissue engineered implants for tracheal reconstruction.

Search Strategy

We searched Pubmed for articles published from January 2000 to September 2019 for the key words “tracheal replacement” or “tracheal substitute” or “tracheal regeneration” or “tracheal tissue engineering” or “tracheal transplantation”. We included only studies in which patients underwent circumferential or near-circumferential (>270°) replacement of the trachea (Table 46.1). We excluded animal model and non-clinical studies. We limited our search to publications in English language and excluded abstracts, conference presentations, editorials, and expert opinions. We included reviews in which new patient information was reported and excluded all retracted articles from our analysis.

Table 46.1 PICO formatted terms for literature search
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Results

An initial search using pre-specified criteria identified 2554 articles. After excluding articles that described solely pre-clinical, animal, or non-circumferential repairs this number was reduced to 25. An additional two articles were excluded due to retraction. Among the remaining 23 articles only 5 employed a tissue engineering approach. In contrast, the other 18 articles employed allotransplantation , autologous tissue, or bioprosthetics reconstruction of the trachea, which will be discussed separately. We included two articles that we view with skepticism given revelations of academic misconduct on the part of the senior author [7, 8]. In all of these reports on tracheal reconstruction, publications have been limited to single case reports or case series. To date, there have been no randomized controlled trials or high-powered observational or cohort studies, and the quality of evidence ranges from low to very low.

Tracheal Tissue Engineering

Tissue engineering is an attractive methodology to provide a solution to organ and tissue shortage. Conceptually, tissue engineering most commonly involves the implantation of a biodegradable scaffold seeded with harvested host cells. After culture in a bioreactor or after direct implantation in the host, a population of stem cells within the seeded cells either differentiates into mature cells or recruits and organizes circulating or adjacent host cells [9]. In either case, this process theoretically leads to repopulation of the graft and replacement of the biodegradable scaffold through deposition of a new extracellular matrix.

This methodology has captured public imagination since its description by Langer and Vacanti [10]. In particular, a tissue engineering approach has enormous potential in pediatric populations , as mature grafts may have the ability to grow with the child into adulthood and spare such patients initial size-mismatch or subsequent reoperation. Tissue engineering has shown some promise in bladder reconstruction and in vascular grafts, but widespread clinical adoption remains limited [11, 12].

Unfortunately, the field of tracheal tissue engineering has been mired by controversy and scientific misconduct. Several reports highlighted the successful clinical translation of a tissue engineering approach [13,14,15]. However, over the last 5 years it has become clear that the reported success of this technique was overstated and many of the patients who underwent these procedures developed devastating complications [7, 16,17,18,19].

In separate reports, two pediatric patients have undergone treatment with tissue engineered tracheal conduits to repair complications of severe congenital airway defects [20,21,22]. The first patient developed a tracheal aortic fistula as a results of recurrent stenting procedures. For this patient, a suspension of cells isolated from bone-marrow aspirate were used to seed a cadaveric tracheal homograft . The tracheal rings of the graft were also injected with tissue transforming growth factor beta and the entire construct soaked in human recombinant erythropoietin and granulocyte colony stimulating factor prior to implantation [20]. Post-operatively the patient required multiple stenting and bronchoscopic procedures, especially within the first year of implantation; however, the graft remained patent with evidence of a ciliated epithelial cell layer in the last reported follow-up at four years [21].

In 2012, a second pediatric patient with multiple congenital abnormalities of the airway and multiple prior interventions underwent treatment with a tissue engineered tracheal conduit [22]. A decellularized cadaveric tracheal graft was seeded over a period of 48 h in a bioreactor with expanded bone marrow-derived mesenchymal stromal cells as well as autologous respiratory epithelial cell obtained from mucosal biopsies of the nasal septum. The graft was supported by a stent, but without a pedicled tissue buttress. While the initial postoperative course was uncomplicated, the patient deteriorated on post-operative day 15 and suffered a prolonged respiratory arrest secondary to airway collapse. This episode was associated with severe hypoxic brain injury and the patient died shortly thereafter.

Alternatives to Tissue Engineering in Tracheal Repair

Alternative methods of tracheal reconstruction have been reported including tracheal allotransplantation, autologous tissue reconstruction, and bioprosthetic repair. Each methodology is associated with its own unique advantages and drawbacks which are compared to tissue engineering in Table 46.2. It is important to state that treatment with radiotherapy alone remains a viable albeit not ideal alternative for patients with adenoid cystic carcinoma and squamous cell carcinoma of the trachea. To date, there has been no randomized controlled trials or direct comparisons between these various methods and the quality of evidence is low to very low. A brief description of each methodology is provided below.

Table 46.2 Comparison of methodology for tracheal reconstruction
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Tracheal Allotransplantation

Tracheal allotransplantation has been challenging due to the segmental blood supply of the trachea, which makes a traditional vascular anastomosis and single stage transplant ineffective [23]. Delaere et al. have sought to overcome these issues through a two-stage procedure, in which the donor trachea is implanted in the forearm of the recipient after being wrapped in a fasciocutaneous flap perfused by a radial vascular pedicle [24]. During this time the recipient is placed on immunosuppressants while revascularization occurs through ingrowth of recipient vessels. After sufficient ingrowth, the tracheal allograft along with the perfusing vascular pedicle can be explanted and implanted in the orthotopic position, while the blood supply is reestablished by anastomosis of the pedicle to the superior thyroid artery and internal jugular vein.

Two stage tracheal allotransplantation has been performed in 6 patients to date [17, 24]. The primary complications have been graft rejection leading to partial loss of the allograft in three patients. Over time, the reported technique has evolved to promote donor repopulation of the mucosa and prevent stricture. Eventually, graft-chimerism may be achieved allowing for withdrawal of immunosuppressants [17, 25, 26].

Autologous Tissue Reconstruction

Autologous tissue reconstruction relies on a well perfused pedicled graft which can be tubularized into a neotrachea [27,28,29,30]. These grafts may be supported by stenting or through implantation of cartilaginous rings harvested and fashioned from costal cartilage. Fabre et al. reported the largest series using this technique, which included 12 patients [29]. Modified versions of this technique have been utilized by two other independent groups in three additional patients [31, 32] .

The results of autologous repair have been mixed. There is generally a need for at least short-term stenting and it is not possible to regenerate airway epithelium, thus the mucociliary escalator is lost. In the series reported by Fabre et al., 58% developed acute respiratory distress syndrome and two patients were tracheostomy dependent. A possible solution is described by Olias et al., who harvest oral mucosal grafts to line the lumen of their neo-tracheas, which may provide some mucociliary function. Unfortunately, this requires a staged procedure and is associated with donor site morbidity [28].

Bioprosthetic Reconstruction

Between 2001 and 2019, aortic interpositional homografts and acellular dermal matrix have been used in circumferential repairs by 5 different groups of investigators in 14 individual patients [33,34,35,36,37,38,39]. The largest study involved 6 patients, in which homografts that were supported internally by a stent and externally by a muscle flap buttress were used to reconstruct the airway in patients with large mucoepidermoid and adenoid cystic carcinomas [35, 37]. Long-term stenting was required in 80% and half encountered major complications such as anastomotic dehiscence, sternal dehiscence, and fungal infection of the graft.

More recently, Martinod et al. have reported tracheal repair in five patients with benign laryngeal tracheal stenosis through aortic homograft reconstruction supported by Nitinol stents and buttressed with strap muscle [38, 40]. Importantly, Martinod preserved the membranous portion of the native trachea in their repair. The authors proposed an “in vivo tissue engineering” mechanism in which retained growth and angiogenic factors within the donor extracellular matrix are released and lead to the migration, proliferation, and differentiation of host cells [38]. In long-term follow-up ranging from 9 months to 7 years all patients remain alive and three have had stents removed.

Conclusions and Recommendations

Tissue engineered tracheal grafts have been associated with significant mortality and morbidity in translation to clinical practice. When possible, primary tracheal resection and reconstruction is the safest form of repair. In rare cases of tracheal pathology that precludes primary repair, allotransplantation, autologous tissue reconstruction, and bioprosthetic repair are viable options and associated with less morbidity and mortality than tissue engineered approaches. The overall quality of evidence remains low and is based on limited case series and case reports.

Recommendation

  • We recommend against the use of tissue engineered trachea for tracheal reconstruction (quality of evidence low; strong recommendation).

A Personal View of the Data

Attempts to replace lost human tissue with synthetic material have been made since the early days of medicine and surgery. In some applications, such as heart valve or joint prostheses, this approach has been very successful. However, three inherent characteristics of the native trachea make it a particularly challenging application : (1) it is in contact with the outside world; (2) it requires excellent blood supply; and (3) it resists the native universal proclivity of most tissues to close a space or orifice. In areas where implanted grafts or devices come in contact with the outside world, colonization and subsequent infection are major limiting factors. Once colonized, a biofilm establishes itself that provides a constant source of reinfection and necessitates graft removal in most cases. Tissue engineering, the concept of creating a living graft that fully integrates in the host similar to a donor organ, could theoretically solve this problem and enable the host’s immune system together with the graft’s inherent barrier function to protect the implant and maintain intricate mechanical properties [10]. In order to do so, any tissue graft of relevant scale would have to be perfused by the recipient’s cardiovascular system. However, to date, no tissue engineering approach has enabled the formation of perfusable tissue, i.e. tissue with intact vasculature [41]. In fact, NASA is currently conducting a Centennial Challenge to increase awareness of this unmet need, and supports research to generate a 1 × 1 cm sized section of perfusable living tissue [42]. As surgeons we learned that transplantation of a living tissue graft thicker than 0.2 mm will require an immediate blood supply or lead to devastating failure. We also learned that implanting a foreign material without tissue coverage and in contact with the outside world will lead to failure. Unfortunately, until technologies are developed that enable the formation of viable, mature (barrier and mechanical stability), and perfusable tissue grafts, we have no option but to continue to use established techniques to treat patients with tracheal disorders.