# Engineered Tracheal Replacements

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $603,077

## Abstract

ABSTRACT:
 The overarching Goal of this proposal is to engineer a replacement airway for patients who must have
their tracheas resected due to injury, infection, or cancer. Diseases of the trachea lead to approximately 4,000
tracheal excisions per year in the United States. But unlike most other connective tissues in the body - such as
blood vessel, bone, skin and tendon - there currently are no replacements for tracheal tissue that are in
widespread clinical use. For small tracheal defects that are less than ~ 5 cm in length, diseased tissue can
generally be excised with primary re-anastomosis of the native trachea. However, this requires putting traction
on the native airway that can lead to risk of ischemia, anastomotic dehiscence, and mediastinitis, which can be
fatal. Furthermore, for longer tracheal defects, there is no approach at all to restore the airway. Therefore, lack
of a suitable tracheal replacement is a Significant medical problem.
 The ideal replacement tracheal tissue would be one that has the mechanical properties of the native
airway (eg. can resist both tensile and compressive forces); does not require immunosuppression; is easily
implantable using standard techniques; can survive the tenuous blood supply of the tracheal environment
without anastomotic failure; and is readily available. Recently, we described a novel engineered, acellular
tissue that fulfills most of these requirements, and which functions for at least two months in several animal
models. However, in approximately 30% of implants in rodents and primates, we have observed mid-graft
fibrotic stenoses that led to airway occlusion, which contained fibroblasts and abundant collagen matrix
deposition, but little epithelial repopulation. The underlying Premise of this application is that undesirable host
remodeling responses lead to the airway fibrosis and stenosis that is seen in a subset of these engineered
tracheas. Specifically, we hypothesize that a trigger of host fibrosis may be the supra-physiological stiffness of
the engineered airways, which can impact the Hippo pathway and TGF-signaling and lead to fibroblast
proliferation and collagen deposition. A second hypothesis is that inadequate epithelial re-population of the
engineered trachea by host basal cells may lead to a lack of local inhibitors of fibrosis, including prostaglandin
E2. This application will explore both of these hypotheses in efforts to improve the long-term functionality of
engineered tracheal replacements. In the long term, the Impact of this work relates to developing a functional
tracheal replacement that could help thousands of patients each year. In addition, we may Impact our
understanding of tracheal stenosis that occurs in other clinical settings.

## Key facts

- **NIH application ID:** 9971550
- **Project number:** 5R01HL138540-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** LAURA E NIKLASON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $603,077
- **Award type:** 5
- **Project period:** 2017-08-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971550

## Citation

> US National Institutes of Health, RePORTER application 9971550, Engineered Tracheal Replacements (5R01HL138540-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971550. Licensed CC0.

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