ENGINEERING A FUNCTIONAL AORTIC HEART VALVE USING A 3D BIOPRINTING APPROACH
Aortic valve disease is one of the most common congenital heart defects and affects over 5% of children with heart disease. Often times, pediatric patients are treated by replacing or less commonly repairing the valve. The issue with clinically available valve implants for children is that they come at a fixed size and are incapable of growth. Thus, this requires multiple surgeries for valve revisions. Our goal is to address this need with a tissue engineered heart valve that is capable of growth and remodeling within a growing child. To do so, we are using induced pluripotent stem cells to generate patient specific valve cells. In addition, we are engineering cell-laden biomaterials to be 3D printed using 3D models generated from patient CT. Using this approach, we will generate a 3D tissue engineered heart valve that has the potential to grow and repair in a child.
3D BIOPRINTED CARDIAC EXTRACELLULAR MATRIX BASED HEART PATCH FOR TREATMENT OF PEDIATRIC HEART DISEASE
Congenital heart defects effect 35,000 newborns annually, resulting in significant hindrance to heart function. Although surgical treatments have shown improvements, many children develop cardiac dysfunction and right ventricular failure. The main standard of care in these cases is transplantation, which is limited by donor availability and transplant rejection. In collaboration with the Christman lab at the University of California, San Diego, we are developing a heart patch, composed of cardiac matrix material and pediatric stem cells, for treatment of pediatric heart failure. The use of cardiac stem cells will allow for targeted and effective regeneration of heart function, while the inclusion of cardiac matrix will decrease hypertrophy and improve ejection fraction. The patch will be bioprinted for control of device structure and properties, allowing for a personalized treatment platform.
USING SYSTEMS BIOLOGY AND BIOINFORMATICS TO IDENTIFY POTENITAL THERAPEUTIC RNA CLUSTERS IN HCPCS
The regenerative potential of cardiac progenitor cells (hCPCs) have been demonstrated in multiple studies indicating the repair of the myocardium following injury. In this project, we will sequence the RNA from a large pool of hCPCs that our lab has accumulated for miRNAs of interest. A bioinformatics/systems biology approach will be used to identify covariant miRNA clusters with respect to several parameters and identify any potential targets of interest for further study. Ideally, we hope to gain insight into the molecular mechanisms by which hCPCs regenerate cardiac tissue.
ENGINEERING EXOSOME-LIKE VESICLES
Stem cell based cardiac regeneration occurs mainly through paracrine signaling to local tissues. A key component of the paracrine signals released by the stem cells are nano-sized vesicles called exosomes. These are vehicles used to transfer microRNA, proteins and lipids to the native tissue. The therapeutic effects of such signaling persists long after the implanted stem cells have been flushed out, highlighting their importance in regenerative therapies. We want to artificially engineer exosomes in-vitro so we can modulate the type and concentration of cargo delivered and also target specific tissues based on membrane proteins we attach. This will provide a highly controllable and specific avenue of paracrine signaling for regenerative therapies.
EXOSOMES FOR MYOCARDIAL REPAIR
Exosomes are vesicles derived from cell membranes which are released either by the fusion of microvescicles with the cell membrane or directly by cell membrane. They carry various signals including micro-RNAs which can serve either as biomarkers or therapeutic agents in treating cardiovascular diseases including myocardial infarction (MI). In this project, we are looking at the effect of exosome delivery on heart function and regeneration in an ischemia reperfusion model of MI.
DEVELOPING A TISSUE-ENGINEERED CARDIAC PATCH FOR CHILDREN'S HEART DISEASE
In collaboration with the Xia Lab at Georgia Tech, we are currently investigating the use of an electrospun polycaprolactone-based cardiac patch to enhance the reparative capabilities of pediatric human cardiac progenitor cells. Specifically, we are interrogating the effects of fiber alignment and the inclusion of bioactive adhesion factors gelatin and fibronectin on cell behavior. We hope to utilize these patches to repair injured hearts and to provide treatment for patients with congenital heart defects.
INVESTIGATING THE ROLE OF NOTCH1 ACTIVATION IN CARDIAC PROGENITOR CELLS
Cardiac progenitor cells (CPCs) are a population of cardiac stem cells that can differentiate to form cardiomyocytes, smooth muscle, or endothelial cells. Because of their regenerative capacity, CPCs are a prime candidate for cell-based therapies to repair the damage caused by myocardial infarction (MI). We are working to improve cell retention and differentiation by designing novel injectable biomaterials for CPC delivery. We are also interested in the importance of the Notch1 signaling pathway in promoting survival and differentiation of CPCs
BIOACTIVE NANOPARTICLES FOR SMALL MOLECULE DELIVERY TO CARDIAC MYOCYTES
Delivery of small molecules to the heart is limited by the ability of cardiomyocytes (CMs) to internalize substances. We have developed a drug delivery system for enhanced CM uptake by decorating degradable, biocompatible, polyketal nanoparticles with N-acetylglucosamine (GlcNAc) and demonstrated their ability to be internalized by cardiac myocytes. In addition to facilitating the delivery of functional small molecules and proteins to CMs, the GlcNAc molecule released from intracellular nanoparticle degradation can be used as a substrate for post-translational modification of calcium handling proteins in myocytes, hence making it a “bioactive” nanoparticle. Thus, the development of our bioactive nanoparticle allows for a “two-hit” treatment, by which the cargo and also the nanoparticle itself can modulate intracellular protein activity.
AGGREGATION OF CARDIAC PROGENITOR CELLS INTO 3D SPHEROIDS TO TREAT MYOCARDIAL INJURY
Specialized cells found in the heart, called cardiac progenitor cells (CPCs), have the ability to repair the injured heart and our lab has developed a method to isolate these cells from human tissue biopsies. While therapies using these cells have been demonstrated in clinical trials to be safe and feasible, their success has been limited by low cellular differentiation and cell retention. We propose the delivery of CPCs aggregated into scaffold-less 3D spheroids. The 3D microenvironment may recapitulate cell signaling interactions found in the cardiac stem cell niche to improve retention and differentiation of CPCs into mature cardiac phenotypes.