Tissue-engineered trachea composites for long-segment airway replacement

Ended Project Grant Awarded Last action

Award ID
R01HL157039
Recipient
Awarding agency
Obligated
$8,814,201

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date
Originally
Funding
  • $8,072,881.00 Federal
  • $741,320.00 Non-federal
Place of performance
Columbus, OH 43205, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Pediatric long-segment airway defects are caused by congenital malformations or result from trauma, infection, or malignancy. Although rare, these defects are often fatal. There is currently no established surgical technique to repair long-segment tracheal defects and the reconstructive options remain heroic. Tissue engineering has the potential to replace failed tissue with a normal, living organ. Despite its potential, clinical outcomes of tissue engineered tracheal grafts (tetg) have been poor. The main barriers to translation of tracheal replacement are graft collapse and delayed epithelialization. We assessed the performance of decellularized tetg (dctetg) in our mouse model of orthotopic tracheal replacement. We identified that decellularized tetg can regenerate, restoring a functional surface airway epithelium (SAE), however outcomes are limited due to graft collapse. Using resorbable biomaterials to stabilize dctetg, we created a composite tetg (ctetg). We hypothesize the ctetg can improve overall survival in long-segment tracheal replacement, attenuate graft collapse, promote extracellular matrix (ECM production) and SAE differentiation. To test this hypothesis, we will first assess how ctetg promotes ECM regeneration in the tracheal cartilage. In our first aim, we will implant dctetg and ctetg in a mouse model of tracheal replacement and quantify ECM production and mechanical properties. Using a conditional knock-out of chondrocyte-mediated ECM production, we will then assess the impact on graft chondrocytes on ECM production. In our second aim, we will define how SAE differentiation is promoted by ctetg. We hypothesize that modification of graft dimensions with splinting reduces wall shear stress (WSS) resulting in improved epithelial differentiation. To test the effect of WSS on SAE differentiation, we will implant dctetg and ctetg of normal and small diameter, thus increasing WSS by reducing graft radius. To quantify WSS, we will use computational fluid dynamics (CFD) to topographically map WSS through the tetg and correlate these values with quantitative immunofluorescence of NEO-epithelium. Finally, we will validate ctetg performance in an ovine model of tracheal replacement in our third aim. Using routine radiographic and endoscopic surveillance, we will quantify animal survival, clinical manifestations, graft dimensions, and graft regeneration. This proposal advances the field of airway tissue engineering through the development of a composite tissue engineered tracheal graft and defining the mechanical factors contributing to graft regeneration.

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Subawards

Subrecipient Amount Awarded
The Ohio State University Dr. Kai Zhao (co-investigator) and this team will be in charge of the computational fluid dynamic analysis of mouse TETG outlined in Aim 2. Dr. Zhao and Dr.… $634,004
Nanofiber Solutions LLC Despite advances in endoscopic and open airway surgery, there is no surgical cure for children with long segment tracheal defects. Consequently, only heroic… $174,285

Quick answers

Who received award R01HL157039?

R01HL157039 was awarded to Research Institute At Nationwide Children's Hospital by National Heart Lung and Blood Institute (National Institutes of Health) on July 16, 2021.

How much is award R01HL157039 worth?

$8,814,201 has been obligated on R01HL157039: $8,072,881 in federal funding and $741,320 in non-federal funding.

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