The History of Engineered Tracheal Replacements: Interpreting the Past and Guiding the Future

Abstract

The development of a tracheal graft to replace long-segment defects has thwarted clinicians and engineers alike for over 100 years. To better understand the challenges facing this field today, we have consolidated all published reports of engineered tracheal grafts used to repair long-segment circumferential defects in humans, from the first in 1898 to the most recent in 2018, totaling 290 clinical cases. Distinct trends emerge in the types of grafts used over time, including repair using autologous fascia, rigid tubes of various inert materials, and pretreated cadaveric allografts. Our analysis of maximum clinical follow-up, as a proxy for graft performance, revealed that the Leuven protocol has a significantly longer clinical follow-up time than all other methods of airway reconstruction. This method involves transplanting a cadaveric tracheal allograft that is first prevascularized heterotopically in the recipient. We further quantified graft-related causes of mortality, revealing failure modes that have been resolved, and those that remain a hurdle, such as graft mechanics. Finally, we briefly summarize recent preclinical work in tracheal graft development. In conclusion, we synthesized top clinical care priorities and design criteria to inform and inspire collaboration between engineers and clinicians toward the development of a functional tracheal replacement graft. Impact statement The field of tracheal engineering has floundered in recent years due to multiple article retractions. However, with recent advances in biofabrication and tissue analysis techniques, the field remains ripe for advancement through collaboration between engineers and clinicians. With a long history of clinical application of tracheal replacements, engineered tracheas are arguably the regenerative technology with the greatest potential for translation. This work describes the many phases of engineered tracheal replacements that have been applied in human patients over the past 100 years with the goal of carrying forward critical lessons into development of the next generation of engineered tracheal graft.

Keywords: clinical outcomes; history; scaffold design; tracheal engineering.

FIG. 1.

Overview of evolution of long-segment tracheal repair methods over time.

FIG. 2.

Patient characteristics. Histograms of (A) patient condition underlying the need for tracheal replacement, (B) patient age, (C) patient sex, and (D) geographic locations of airway procedures.

FIG. 3.

Clinical application of graft types over time. Dot plot of the number of patients receiving each type of tracheal replacement graft.

FIG. 4.

Examples of scaffold types used in patients. Gross images of each type, adapted from cited publications: (A) skin or fascia only (Fabre et al.), (B) rigid polymer tube (Clagett et al.), (C) wire/mesh/gauze (Ellis et al.), (D) metal (or glass) tube (Cotton and Penido), (E) silicone tube (Neville et al.), (F) heterotopic/orthotopic allotransplant (Delaere et al.), (G) treated or preserved allograft (Jacobs et al.), (H) aortic autograft/allograft (Wurtz et al.), and (I) decellularized allograft (Elliott et al.). Red dotted boxes added to aid visualization of graft. Images reproduced from cited articles with permissions from Elsevier, Wiley, and associated journals.

FIG. 5.

Maximum reported follow-up time by tracheal graft type. Pairwise statistical comparisons were made by Welch's t-tests (**p < 0.01, ****p < 0.0001). Number of patients per condition (n) indicated on data bars in white. Error bars represent SEM. SEM, standard error of the mean.

FIG. 6.

Causes of mortality in patients receiving tracheal replacement grafts.

FIG. 7.

Critical care priorities and design criteria for a successful engineered trachea, synthesized from clinical experience summarized in this review, and compared to the Grillo Design Criteria.