The trachea: The first tissue-engineered organ?

In reports on bioengineered tracheas, it is frequently stated that the trachea is well suited to tissue engineering because it consists of a hollow, relatively simple structure. In reality, however, the trachea has an ingenious morphology that allows it to fulfill its function (Figure 1, A). It is thus one of the most difficult organs of the human body to replace. To date, regeneration within the airway tract is only possible for epithelial defects above the basement membrane. If a tissue injury is severe and involves damage to both epithelial cells and the submucosal layer, healing will be accomplished by secondary intention, leading to stenosis of the airway (Figure 1, B). The current challenge for regenerative medicine is to overcome barriers to regeneration of the epithelial lining in full-thickness mucosal defects, which is not yet possible (Figure 1, C).

Tracheal regeneration for airway repair with bioengineered constructs typically consists of a cartilaginous tube lined with viable respiratory mucosa.^,  These constructs are created with bone marrow stem cells and growth factors (of which the clinical value for tissue healing is unknown) that are applied to a nonvascularized scaffold. The mechanism behind the transformation from nonviable construct to viable airway cannot be explained with our current knowledge of tissue healing, tissue transplantation, and tissue regeneration. In fact, cells have never been observed to adhere, grow, and regenerate into complex tissues when applied to an avascular or synthetic scaffold. Moreover, this advanced form of tissue regeneration has never been observed in laboratory-based research.

Of the 14 patients who have received bioengineered tracheas, 3 have been described in case reports in 4 different articles (the first patient was described after both 6-month and 5-year follow-ups).^{,  ,  ,}  In these articles, 2 different scaffolds (2 cases with an enzymatically decellularized tracheal allotransplant^{,  ,}  and 1 case with a synthetic nanocomposite) were reported as being used, along with 2 different techniques of applying bone marrow cells to the scaffold (2 cases with a bioreactor for “ex vivo” use^{,  ,}  and 1 case where the bone marrow cells were applied “in vivo”). Production of the bioengineered trachea in all cases produced similar results, and the different approaches worked in comparable ways. Information gathered from published reports on these 3 patients and unpublished reports on an additional 11 patients suggests that mortality and morbidity were very high. More than half of the patients died within a 3-month period, and the patients who survived longer functioned with an airway stent that preserved the airway lumen.

From this information, it can be concluded that the bioengineered tracheal replacements were in fact airway replacements that functioned only as scaffolds, behaving in a similar way to synthetic tracheal prostheses. In recent years, most synthetic materials used for tracheal replacement have been tested in experimental animal research. From these studies, it became clear that definitive prosthetic replacement of the airway wall is not possible. To date, nearly all surgical prostheses that have been successful were observed in potentially sterile mesenchymal tissues. No example of successful prosthetic repair can be cited in the respiratory, gastrointestinal, or genitourinary tract. The internal site of the airway tract belongs to the outside world, and bacterial contamination at the interface between the airway and prosthesis prevent its ingrowth (Figure 2). The complications of wound breakdown at the anastomoses can be temporarily delayed by wrapping the prosthesis in vascularized tissue, mostly transposed omentum. This is exactly what occurred in nearly all cases of the supposedly bioengineered tracheal replacements. The scaffolds were wrapped in vascularized omentum so that inevitable complications could be delayed. In patients who survive for longer periods, granulation tissue will form at the suture lines, a complication that necessitates placement of a stent to preserve the airway lumen temporarily (Figure 2, E).

It seems contradictory that one of the most difficult organs to replace has been reported as being the first bioengineered organ. How can a synthetic tracheal replacement, destined to fail, be described as a major breakthrough in organ tissue engineering?

The dissemination of misleading information regarding bioengineering of complex tissues would not be possible in tissues that can be directly visualized (Figure 3). For a tracheal replacement, direct visualization of the transplant and subsequent healing is only possible in an experimental setting and during autopsy. Neither of these methods, however, were used to document the tissue-engineered tracheas in the 14 previous patients. Tracheal bioengineering was not tested in animal models, and despite the fact that several patients died after having received the bioengineered tracheal replacement, no postmortem histologic data have been published. Although in vivo visualization of tracheal transplants and their healing process is possible with serial computed tomographic scanning and endoscopic imaging performed at regular intervals after implantation, clear visualization of the transplant is lacking in all reports regarding the bioengineered trachea. Published computed tomographic images and endoscopic views show only images produced shortly after transplantation and either do not allow the clear visualization of the transplant or were obtained with an airway stent in place.^{,  ,  ,}  In an editorial in Science discussing the controversy of this topic, the main scientist behind the bioengineering approach acknowledged that “it was difficult to tell what exactly had happened inside the implanted tracheas,” which is remarkable when considering the high-quality computed tomographic scans and endoscopic approaches that are currently available.

The media hype regarding “stem cells” and the work done on an airway that is less accessible for direct visualization are key elements that explain publication of these papers in highly ranked medical journals.^{,  ,  ,  ,} 

In conclusion, the ethical justification of tracheal replacement with a synthetic prosthesis or with a decellularized allograft in humans is questionable, because there are no available experimental data describing a possible successful outcome. The currently available published articles on bioengineered tracheas and the resulting media attention endanger the field of tracheal replacement and the field of tissue engineering as a whole. For patient safety, tracheal bioengineering must be demonstrated as being efficacious and safe before further transplants.