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Regenerating the trachea after intubation trauma: the role of tissue-engineering in a post-COVID era

Injuries on the orotracheal canal are common during endotracheal intubation and may lead to potentially life-threatening complications. In some cases, surgical interventions become necessary to correct serious damage caused to the larynx and trachea. There are several types of larynx injuries, caused by multiple mechanisms, but mostly, they are consequences of the permanence of the tube in direct contact with the structures of the aerial ways of the patient. The endotracheal intubation is often performed in critically ill or anesthetized patients to facilitate ventilation of the lungs, including the mechanical ventilation to prevent airway obstruction and suffocation [1,2].

Figure 1: Endoscopic view of a postintubation tracheobronchial laceration [2].

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been spreading globally after the first respiratory cases appeared in Wuhan, China, in December 2019. In this scenario, global health care is experiencing an unprecedented rise in the number of critically ill patients who need mechanical ventilation. The clinical management of the most severe cases require tracheal intubation to provide ventilatory support [3,4]. Current evidences indicate that approximately 15% of patients required invasive mechanical ventilation (IMV). Moreover, data demonstrate that COVID-19 patients needed an average of 17 days of IMV, with a high frequency of re-intubation [5].

Regenerative medicine and tissue engineering techniques have opened up a new path for reconstructing damaged tracheal tissue. The trachea is a complex organ due to its particular mechanical properties and specialized function and, in order to achieve a functional organ replacement in the clinic, it is very important to develop appropriate procedures, techniques, and ideal cell culture and biomaterial conditions [6,7]. With advances in 3D bioprinting techniques, it is now viable to design a customized tracheal model with a morphology that is suitable for the patient and capable of maintaining the original shape and morphology of the engineered trachea. Biocompatibility, biodegradation, non-toxicity, and non-immunogenicity are essential features of a successfully engineered organ [8].

Last year, a study attempted to create an effective artificial trachea via a tissue engineering method using 3D bioprinting. A multi-layered scaffold combining synthetic and natural polymers and cells from different sources was fabricated using a 3D bioprinter. Polycaprolactone (PCL) and an alginate hydrogel were used with autogenous nasal epithelial and auricular cartilage cells for the printing process. In the in vivo assay, the bioprinted artificial trachea was transplanted into 15 rabbits and a PCL scaffold without the addition of cells was transplanted into 6 rabbits. Thirteen of fifteen animals survived until 12 months without specific respiratory signs in the experimental group, while the control group showed the survival of only four out of six animals. Neonatal cartilage was also confirmed at 6 and 12 months, demonstrating that the artificial trachea successfully resulted in epithelialization and formation of cartilage islet [9].

Figure 2: (A)Picture of the partially resected trachea. The ventral part of the resected trachea is a semi-circular shape. (B) The artificial trachea is cut into semi-circular shapes and placed with interrupted sutures [9].

It is important to emphasize that patients with COVID-19 have their respiratory epithelial cells covering the airways and alveoli very damaged, since these structures are the major targets of the virus. This damage to the epithelium can be exacerbated by the use of mechanical ventilation, thus it is expected that many of the infected patients that survived the acute phase will develop pulmonary diseases if the epithelium fails to regenerate properly. Therefore, regenerating the trachea after intubation trauma through tissue engineering in a post-COVID era can be an interesting approach to bring more quality of life to individuals affected by this disease [10].


1- Mota LA, de Cavalho GB, Brito VA. Laryngeal complications by orotracheal intubation: Literature review. Int Arch Otorhinolaryngol. 2012;16(2):236-245.

2- Giuseppe Cardillo, Luigi Carbone, Francesco Carleo, Sandro Batzella, Raffaelle Dello Jacono, Gabriele Lucantoni, Giovanni Galluccio, Tracheal lacerations after endotracheal intubation: a proposed morphological classification to guide non-surgical treatment, European Journal of Cardio-Thoracic Surgery, Volume 37, Issue 3, March 2010, Pages 581–587.

3- Abou-Arab O, Huette P, Berna P, Mahjoub Y. Tracheal trauma after difficult airway management in morbidly obese patients with COVID-19. Br J Anaesth. 2020;125(1):e168-e170.

4- McGrath, B. A., Brenner, M. J., Warrillow, S. J., Pandian, V., Arora, A., Cameron, T. S., … Feller-Kopman, D. J. (2020). Tracheostomy in the COVID-19 era: global and multidisciplinary guidance. The Lancet Respiratory Medicine.

5- Mattioli F, Marchioni A, Andreani A, Cappiello G, Fermi M, Presutti L. Post-intubation tracheal stenosis in COVID-19 patients [published online ahead of print, 2020 Oct 3]. Eur Arch Otorhinolaryngol. 2020;1-2.

6- Kojima, K., & Vacanti, C. A. (2013). Tissue Engineering in the Trachea. The Anatomical Record, 297(1), 44–50.

7- Baiguera, Silvia1; Birchall, Martin A.2; Macchiarini, Paolo1,3 Tissue-Engineered Tracheal Transplantation, Transplantation: March 15th, 2010 - Volume 89 - Issue 5 - p 485-491

8- Frejo, L., Grande, D.A. 3D-bioprinted tracheal reconstruction: an overview. Bioelectron Med 5, 15 (2019).

9- Park, JH., Yoon, JK., Lee, J.B. et al. Experimental Tracheal Replacement Using 3-dimensional Bioprinted Artificial Trachea with Autologous Epithelial Cells and Chondrocytes. Sci Rep 9, 2103 (2019).

10- Fang, Y., Liu, H., Huang, H. et al. Distinct stem/progenitor cells proliferate to regenerate the trachea, intrapulmonary airways and alveoli in COVID-19 patients. Cell Res 30, 705–707 (2020).

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