The Development of Cardiac Extracellular Matrix - Silk Fibroin-Based Engineered Cardiac Tissue Repair of Congenital Heart Defects in Pediatric Patients
Abstract
This proposal addresses the Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area of Congenital Heart Disease. Congenital Heart Disease affects ~1% of all live-born babies in the United States, and the most severely affected often require surgery within the first few days of life in order to survive. Recent epidemiological studies indicate that there is an increased prevalence of congenital heart disease among the children conceived by Veterans returning from the first Gulf War. Due to advancements in surgical techniques and post-operative care, many of these patients are living significantly beyond the operative period; however, those with the most severe congenital heart defects (CHDs) usually end up with heart failure in early adulthood and often require a total heart transplant to survive. The majority of these heart failure cases are due to the failure of the right side of the heart (which normally pumps blood to the lungs to be re-oxygenated), primarily because many of the severe defects involve a narrowing of the great vessel that takes blood from the right side of the heart to the lungs (called the right ventricular outflow tract, or RVOT). Surgeries to reconstruct and widen this area of the heart to allow more blood to pass through are currently carried out using synthetic plastic patches that do not accurately reflect the properties of normal cardiac muscle. As such, these patches are prone to further complications and often require secondary operations as they are non-living and thus do not grow with the child. The goal of the research proposed herein is to develop a new kind of living tissue patch that is based on two important biological materials: (1) silk and (2) a collection of the proteins that make up the support structure of the heart, called the extracellular matrix or ECM. Silk is a natural material that is derived from the cocoons of silk worms and it is already Food and Drug Administration approved for a number of uses in the human body due to its biocompatibility and the ability to make a variety of formats from the starting material. The proteins of the ECM play an important role in signaling the cells present in the heart to function normally. By combining these two materials, we are seeking to develop a new biomaterial that promotes the growth of cardiac muscle cells derived from the patient in order to create new cardiac tissue to be implanted to repair of the RVOT in CHD patients, with the patch eventually degrading, leaving only native tissue in its place. To develop this new material, we will carry out a set of experiments in the lab testing the response of a variety of cell types that are present in the heart to various formulations of the material. We will also assess the ability of patient-specific cardiac muscle cells generated from stem cells to generate functional tissue in the material. Once we have defined a set of optimal formulations, we will then generate tissues and implant them in the heart in a small animal model that mimics the RVOT repair surgery. This will allow us to test the design of our new tissue patch to ensure that it functions as we expect. If it does not, we can iterate on the design by altering some of the properties based on the results of the first set of experiments on the heart cells. In the last part of the proposed work, we will test the optimized material design from the experiments in the small animal surgeries as a tissue patch in a large animal model of RVOT repair (pigs). Here again we will assess the formation of new tissue in the patch, the integration of the patch with the native tissue, and the function of the heart following patch implantation. Ultimately, we expect to develop a new living tissue patch for cardiac repair of patients with CHDs. We anticipate that by promoting tissue formation and growth of the patient specific cells this new tissue patch will outperform the current patch materials in terms of its abilit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610304
Entities
People
- Lauren Black
Organizations
- Tufts University
- United States Army