CURRENT RESEARCH

The research goals of our lab are the following: 1) use cell and tissue engineering techniques to develop novel experimental modalities that flexibly mimic the structure of both healthy and diseased hearts at multiple organizational levels from single cell to two- and three-dimensional cell networks, 2) apply genetic, pharmacological, and electrophysiological spatio-temporal alterations to study physiological, pathophysiological and developmental structure-function relationships in cardiac muscle, and 3) utilize these studies to identify possible targets for novel antiarrhythmic therapies and to improve design rules for gene and cell transplantation treatments of the diseased heart. Specific projects include:

1. Cell and tissue engineering of 2-D and 3-D cardiac cellular networks that mimic architectural and functional properties of healthy heart muscle.

In addition to the development of techniques for uniform anisotropic growth of cardiomyocytes on macroscopic 2-D surfaces, we are currently establishing methodologies for the design of an in vitro model system for studies of intramural cardiac function by engineering a cell culture with anatomical and functional characteristics of an arbitrary slice from a native heart, including realistic size and geometry of the heart walls and chambers, local cardiac fiber orientation, and patterns of electrical propagation.

We are also using variety of microfabrication techniques, different types of hydrogels as well as tissue culture bioreactors that deliver biomimetic regimes of mechanical stimulation in order to develop 3-D, anisotropic, multilayer cardiac cell cultures for experimental studies and potential implantation in the damaged heart.

2. Design of cardiac cellular networks that mimic the architectural and functional phenotype of diseased heart muscle.

This project aims to develop cell networks that mimic pathological alterations in cardiac tissue architecture and composition encountered in heart failure, ischemia, or infarction, and study their effect on electrical impulse conduction, formation of wavebreaks and genesis of arrhythmias. Some of the most important pathological changes in diseased myocardia include the presence of fibrosis (deposition of interstitial collagen and increased number of fibroblastic cells), altered degree of intercellular coupling and anisotropy, cellular hypertrophy, and changed expression of different contractile and ion channel proteins.

3. Experimental and theoretical studies in cardiac cellular networks on the role of structural and functional heterogeneity in cardiac arrhythmogenesis.

Local or global heterogeneities in cell type and/or ion channel function are genetically or pharmacologically introduced in cardiac networks with predefined physiological or pathological architecture. These networks are used to systematically study the effect of heterogeneous cardiac substrate on initiation, spatio-temporal dynamics, and termination of cardiac reentry. Computer models that incorporate cardiac cell geometry, distribution of intercellular connections, discrete tissue microarchitecture, and electrical cell membrane properties are implemented in order to directly match the computational and experimental studies in 2-D and 3-D cardiac cellular networks.

4. Cardiomyoplasty in vitro - host/donor cell interactions

Initial clinical studies with autologous skeletal myoblasts and bone marrow cells show promising results but lack insights in the intrinsic potential of implanted cells to electro-mechanically couple with, and/or possibly alter the function of host cardiac tissue. The main goal of this project is to systematically study both direct and paracrine interactions between different cell types (i.e. fibroblasts, skeletal myoblasts, mesenchymal or embryonic stem cells) and cardiomyocytes, and to evaluate the underlying mechanisms by which the donor cell implants can improve or deteriorate the electro-mechanical activity of host cardiac networks in vitro.