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.

The Growing Medical Need for Tracheal Replacement: Reconstructive Strategies Should Overcome Their Limits

“…Historically, tracheal reconstructive approaches involving rigid polymer constructs, glass or metal prosthesis, or more flexible materials such as polymeric or metallic wire/meshes, and silicone, have always been unsuccessful in clinical practice ( Greaney and Niklason, 2021 ). Indeed, rigid polymer constructs or prostheses, despite remaining patent, are challenging to be properly sutured and often shifted out.…”

“…However, the lack of integration with the surrounding tissue, granulation formation and haemorrhages due to graft mobilization strongly limited their clinical diffusion ( Neville et al, 1976 ; Neville et al, 1990 ; Toomes et al, 1985 ; Schneider et al, 2001 ). Finally, polymeric or metallic wire/meshes have also been adopted as tracheal substitutes, displaying unsafe and ineffective outcomes ( Greaney and Niklason, 2021 ). Indeed, besides the usual granulation tissue formation, scaffold migration with erosion of the surrounding vessels and oedema, these prostheses lack adequate mechanical properties, leading to airway narrowing and collapse ( Clagett et al, 1948 ; Kramish and Morfit, 1963 ).…”

Role of Collagen in Airway Mechanics

“…Regenerative medicine has adopted the use of acellular airway constructs through decellularization in an effort to provide a biomimetic scaffold for tissue engineering. However, decellularization of a multi-lineage tissue (bearing epithelial, vascular, muscle, and cartilaginous structures) such as the trachea has resulted in ECM injury, loss of graft mechanical properties, and collapse in both pre-clinical and clinical applications [ 27 , 28 ]. New approaches to tracheal tissue engineering have focused on the preservation of the native ECM, most importantly its collagen content [ 29 , 30 ].…”

Regeneration of partially decellularized tracheal scaffolds in a mouse model of orthotopic tracheal replacement

“… 4 Approaches for tissue engineered tracheal graft fabrication have included the modification of allograft tissue as well as synthetic and decellularized scaffolds. 5 Allograft outcomes have been limited due to graft immunogenicity and synthetic tracheal scaffolds have exhibited poor epithelialization and neovascularization. 6 , 7 Initially, decellularization was geared toward removal of all native cellular material, thus limiting immunogenicity while preserving a natural scaffold composed of extracellular matrix (ECM).…”