Project summary
Congenital diaphragmatic hernia (CDH) is a serious birth defect characterized by incomplete development of the
diaphragm. This results in a defect in the diaphragm through which abdominal organs, such as the intestines
and stomach, can herniate into the chest. This can cause compression of the lungs and impairs their
development, which can result in fatal pulmonary hypoplasia. CDH affects all races and ethnicities. In the United
States alone, five children are born with this birth defect every day, and one of every three newborns with this
devastating condition dies. CDH treatment requires surgical intervention to return the herniated organs to the
abdominal cavity and to repair the defect. In some cases, the defect in the diaphragm can be closed by suturing
the diaphragm edges together. However, if the defect is too large or if portions of the diaphragm are completely
missing, a prosthetic patch must be used to fix the defect. These patches are most made of synthetic, biologically
inert/inactive materials like polypropylene mesh, reinforced silastic sheet, polyethylene mesh and
polytetrafluoroethylene (trade name Gore-Tex). However, as synthetic patches do not grow with the child,
dehiscence and recurrent herniation are common. Biodegradable synthetic patches, such as polylactide, are
mechanically incompliant and possess insufficient regenerative potential. Decellularized tissue patches, such as
small intestinal submucosa (SIS) and decellularized diaphragm, are mechanically weak and degrade rapidly. To
address these problems, we aim to develop a novel biodegradable, bioactive, elastic patch that not only matches
the mechanical properties of the native diaphragm but also comes with regenerative potential for CDH repair.
Specifically, a biodegradable elastic polymer and decellularized porcine diaphragm will be combined to form a
fibrous patch. The polymer will provide robust mechanical support with elasticity and controllable degradation
while the decellularized diaphragm extracellular matrix (ECM) will offer diaphragm tissue-specific bioactivity to
support cell and tissue growth. This novel patch will be able to move with respiration along with the native
diaphragm and more importantly will grow with the child. Two aims are proposed in this study. In Aim 1, we will
systematically characterize the biomechanics and bioactivity of the native diaphragm, and then develop a fibrous
patch that contains diaphragm-specific ECM bioactivity and mechanically matches the native diaphragm. In Aim
2, we will use an established surgically created diaphragmatic defect rat model to evaluate the in vivo and ex
vivo diaphragmatic functions of the novel patch. This project is innovative and translational, as successful
completion of this project will establish a new methodology to generate a biodegradable, elastic and bioactive
diaphragmatic patch, and provide a novel therapeutic strategy to treat children born with CDH.