Human Tissue Engineered Pulsatile Conduits for Treatment of Single Ventricle Congenital Heart Defect
Abstract
The Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Area under which the application was submitted is “Congenital Heart Disease.” Congenital heart defects are problems with the hearts structure that occur during development and remain present at birth. This class of developmental issues are the most common type of birth defect in the United States. Each year, more than 35,000 babies in the U.S. are born with heart-related birth defects. Single ventricle anomalies are one of the more common forms of heart-related birth defects, affecting approximately 1 in 1,000 live births. Normally, the heart is divided into four distinct chambers. The two chambers known as ventricles are responsible for pumping blood out of the heart and into the lungs (right ventricle) or out to the body (left ventricle). A child with a single ventricle defect is born with a heart with only one of these two ventricles. This can lead to the mixing of oxygen rich and poor blood, which will cause issues in other tissues due to less oxygen reaching them. Additionally, these patients are at an increased risk of heart failure due to the additional stress taken on by the one ventricle doing the work of two. Children born with these defects have a 70% chance of premature death if there is no appropriate surgical intervention. The medical interventions require a series of operations known as the modified-Fontan procedure. The final procedure in this series of operations requires the use of a synthetic vascular conduit or a tissue-engineered vascular conduit to help reroute blood returning to the heart. This allows for a complete separation of oxygen rich and poor blood within the heart, before returning to the body. Although this surgical procedure has markedly increased patient survival, synthetic or engineered vascular conduits employed lack pumping ability and thereby results in insufficient blood flow to tissues, heart failure, and pulmonary vascular diseases in these patients. Thus, there is an urgent need of a tissue-engineered conduit that can generate enough pressure to pump blood into lung. The discovery of human induced pluripotent stem cells (hiPSCs) has revolutionized stem cell research. hiPSCs resemble human embryonic stem cells (hESCs) and have great potential as medical therapies, while avoiding the ethical controversies of using cells from a human embryo. In addition, hiPSCs can also be directed to become any cell type of the body. Because they are derived from a person’s own cells, such as skin or blood cells, they do not cause an immune rejection response and can be used to generate tissue-engineered grafts the patient’s body will recognize as its own tissue. A working design strategy for preparation of tissue-engineered pulsatile conduits (TEPCs) was developed with a previous seed grant from the Department of Defense, which this new proposal intends to improve upon. Currently, our group has produced functional TEPCs by wrapping contracting engineered heart tissue (EHT) around a cell free vascular scaffold. Preliminary results of this design strategy have shown these TEPCs capable of producing an increase in pressure, which has a direct impact in the rate of blood flow. The current project proposes to build upon our previous work by training the cardiomyocytes (muscle cells of the heart) derived from hiPSCs with our engineered tissue to improve the pumping activity of these tissue-engineered pulsatile conduits. The hiPSC-derived heart muscle cells often display fetal heart-like characteristics. This includes the contractile force output of these cells. Many bioengineers use specialized devices known as bioreactors to train hiPSC-derived tissues and develop more adult like behaviors. Our group’s TEPCs will be trained in a bioreactor system that provides electrical and mechanical stimuli that mimic the natural environment these heart muscle cells develop in. This biological mimicking strategy is expect
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910557
Entities
People
- Yibing Qyang
Organizations
- United States Army
- Yale University