Review Article
Tissue-engineered trachea: A review

https://doi.org/10.1016/j.ijporl.2016.10.012Get rights and content

Abstract

Tracheal replacement is performed after resection of a portion of the trachea that was impossible to reconnect via direct anastomosis. A tissue-engineered trachea is one of the available options that offer many advantages compared to other types of graft. Fabrication of a functional tissue-engineered trachea for grafting is very challenging, as it is a complex organ with important components, including cartilage, epithelium and vasculature. A number of studies have been reported on the preparation of a graftable trachea. A laterally rigid but longitudinally flexible hollow cylindrical scaffold which supports cartilage and epithelial tissue formation is the key element. The scaffold can be prepared via decellularization of an allograft or fabricated using biodegradable or non-biodegradable biomaterials. Commonly, the scaffold is seeded with chondrocytes and epithelial cells at the outer and luminal surfaces, respectively, to hasten tissue formation and improve functionality. To date, several clinical trials of tracheal replacement with tissue-engineered trachea have been performed. This article reviews the formation of cartilage tissue, epithelium and neovascularization of tissue-engineered trachea, together with the obstacles, possible solutions and future. Furthermore, the role of the bioreactor for in vitro tracheal graft formation and recently reported clinical applications of tracheal graft were also discussed. Generally, although encouraging results have been achieved, however, some obstacles remain to be resolved before the tissue-engineered trachea can be widely used in clinical settings.

Introduction

The loss and damage of a tissue/organ resulting from an injury or disease can cause serious health problems, as the transplantation of tissue/organs in these patients is extremely limited due to the lack of donors [1]. This situation seriously deteriorates the patient's quality of life and increases the medical and social costs. Even if a patient is fortunate enough to receive an allograft, lifelong immunosuppression is essential. Alternative treatments such as mechanical devices or artificial prostheses do not restore tissue/organ function. In addition, artificial implants suffer from the shortcomings of having a limited lifespan and may promote allergic reactions due to material abrasion [2].

Dissatisfaction with conventional therapies has led to a shift in interest to a relatively new discipline called tissue engineering. Tissue engineering is defined as an interdisciplinary field that applies the principles of bioengineering, materials science and life sciences toward the assembly of biological substitutes that restore, maintain or improve tissue/organ function [3]. The success in creating functional engineered tissues lies in the integration of cells, biomaterials and signaling systems, also known as the tissue engineering triad [4]. Another important aspect that is essential for successful tissue formation in vitro is the bioreactor, which should provide perfusion and physical stimuli to improve cell viability and tissue function.

Stem cells are a key component of tissue regeneration due to their ability to proliferate and self-renew. Stem cells can be recruited to the injured area via two mechanisms: incorporation into an engineered tissue or attraction to the wound site with the help of biomaterials and/or soluble factors (including growth factors, chemokines and cytokines). The development of a scaffold requires the selection of the right biomaterials and fabrication methods, as tissue formation is greatly affected by biocompatibility, bioactivity (e.g. cell attachment, proliferation and differentiation), mechanical properties, architecture (e.g. sheets, fleece and fibers) and the 3-D environment (e.g. porosity, pore size and pore interconnectivity) of the scaffold. The scaffold must possess the appropriate degradation rate that matches the tissue formation rate, with non-toxic degradation products. Bioreactors can provide mechanical stimuli to cells that mimic in vivo conditions. These mechanical cues are important in regulating cell function and tissue remodeling, to produce an engineered tissue that closely resembles the native tissue. Furthermore, bioreactors help with nutrient perfusion, which is crucial in supporting cell survival in a 3-D construct.

The trachea or windpipe acts as a conduit for ventilation and to clear tracheal and bronchial secretions. Severe injury or damage to the trachea can result in a significant decrease in quality of life due to problems with breathing, speaking and swallowing. Direct anastomosis is impossible when a tracheal segment longer than 6 cm needs to be resected due to the high mechanical tension at the anastomosis site, which can lead to severe and fatal postoperative complications [5], [6]. Conventionally, there is no satisfactory solution to this disorder. Although an allogeneic trachea can be used as a replacement, this is accompanied by the shortcoming of lifelong immunosuppressant therapy, which greatly increases the risk of infection. Tracheal xenografts also suffer from the same disadvantage. Currently, tissue engineering has emerged as a potential alternative to tackle this problem. Reconstruction of the trachea requires a layer of ciliated epithelium supported by a laterally rigid but longitudinally flexible tube [7]. The “new” tissue should be able to self-repair, remodel, revascularize and regenerate, without the risk of rejection [8].

A number of studies on tissue-engineered tracheae have been published. Investigators have come out with plenty of new findings that may make inroads toward the clinical application of tissue-engineered tracheae. Nevertheless, there are still some obstacles that need to be overcome before this becomes reality.

Section snippets

Formation of tubular cartilage tissue

Cell-scaffold interactions have a great influence on cell behavior [4]. A good scaffold should possess properties that support cell adhesion, migration, proliferation and differentiation. The scaffold should also be able to promote tissue regeneration and remodeling, without eliciting an inflammatory or immunogenic response which may compromise healing [9], [10]. The scaffold is fabricated into a 3-D porous structure to allow seeded cells to penetrate, attach and proliferate, as well as to aid

Bioreactors for tracheal tissue engineering

Bioreactors have played a pivotal role in the field of tissue engineering because they assist in the interaction between cells and biomaterials. Bioreactors allow the production of large and thick tissue-engineered constructs that cannot be achieved using conventional static culture systems. Bioreactors can provide a dynamic culture environment that gives physiological and mechanical stimuli mimicking the in vivo conditions. The operation conditions (such as pH, temperature, oxygen tension,

Clinical transplantation

Nowadays, more than a dozen clinical tracheal transplantations have been performed [93]. However, not all the patients who received the transplant regained a normal life, and some of the recipients died due to the underlying disease not related to transplantation.

In 2008, Macchiarini et al. reported the world's first clinical transplantation of a tissue-engineered trachea in a 30-year-old woman [87]. The tissue-engineered trachea was made of decellularized human trachea seeded with recipient

Problems faced

Although several research groups have reported that patients with a clinically transplanted tissue-engineered trachea successfully regained anatomical structure and physiological function, there are still some obstacles that need to be addressed before this technique can be used routinely in the clinical setting. Macchiarini incident clearly showed that the clinical use of synthetic tissue-engineered trachea is still not feasible. More preclinical animal studies have to be performed in order to

Future perspectives

Although decellularized tracheal grafts are more commonly used clinically to replace a diseased trachea, the decellularized scaffold is difficult to produce in bulk due to donor shortages. Furthermore, the quality of the decellularized scaffold may vary. Thus, a tissue-engineered trachea made of biodegradable materials is a more promising choice for tracheal replacement. Non-biodegradable materials are not suitable for the fabrication of a tracheal scaffold for pediatric patients as this may

Conclusion

Tracheal replacement is often not a life-saving procedure, but it can greatly reduce patient morbidity and suffering. Among all these methods, tissue-engineering is still the method of choice due to the fact that grafts can be fabricated in bulk, with a relatively low cost, in less time and with no need for second surgery at the donor site. The reported clinical trials have demonstrated that transplantation of a tissue-engineered trachea seeded with autologous stem cells is feasible. However,

Conflict of interests

The authors declare that there are no conflicts of interest.

Acknowledgments

RBHI and ABS were supported by grants from the Ministry of Education of Malaysia, Ministry of Science, Technology and Innovation (MOSTI) of Malaysia and Universiti Kebangsaan Malaysia.

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