Warren Ruder — 2007-08 Fellow
Congestive heart failure is one of the leading causes of death in the western world and its treatment is complicated by the inability of the heart to regenerate its muscle cells following trauma. Injection of stem cells harvested from an adult patient’s own body into the heart has shown promising effects in returning some heart function, but the mechanisms of this recovery process are widely-debated. Common hypotheses include the function of the stem cell as a “homing beacon” for endogenous body repair processes as well the transdifferentiation of stem cells into new cardiac muscle cells.
While it is appreciated that mechanical function of the heart can be potentially restored, the local environment of the stem cell and its effect on this restorative process offer avenues for engineering and optimization. Specifically, if this environment could be controlled, and the local structural mechanics of the cell’s environment improved, overall cardiac function could potentially be addressed from a cellular mechanics perspective.
Local chemo-mechanical control will offer benefits over typical approaches to engineering the cardiac stem cell regeneration process. These other approaches include the pretreatment of cells with growth factors as well as mechanical stimulation of the cells prior to injection. Controlling both the chemistry and mechanics in real-time, in vivo could offer dramatic benefits and opportunities for enhancing cardiac function after stem cell injection.
Additionally, we can take a step beyond traditional medical studies focused on multiple injections of cells in laboratory animal models followed by histological sampling of harvested organs. By designing in vitro analogs to the in vivo environment, techniques for local control can be evaluated.
Our main objectives are as follows:
Objective 1: Create in vitro systems for chemical and mechanical control of the stem cell and cardiac environment. This system will focus the measurement of calcium in cardiac fibers during cell stressing – a direct, cell-specific fingerprint of muscle fiber function.
Objective 2: Create micro-scale, implantable structures allowing for both the in vivo continuous perfusion of cardiac subdomains with cells and chemicals, as well as mechanical interaction of the structure itself with the cardiac microenvironment. These structures will form an implantable biomedical device therapy.
Our first objective will be addressed by the measurement of cell calcium levels (directly coupled to cardiac fiber contraction) by realistically applying force to subdomains of stem cells cultured with cardiac cells. Additionally, we will develop a 3-D fibrous analog to the cardiac microenvironment allowing for stressing of cells in a fibrous environment similar to the heart.
Our second objective will be addressed by the development of micro-scale, hollow, and precision-positioned fibers within the tissue environment. In addition to allowing for the constant flow of chemical and cell therapeutic regimes, the micromechanical interaction with neighboring heart tissue will allow us to regulate the stress in the immediate vicinity for enhanced engraftment. This system can be evaluated with our in vitro techniques developed in the first objective.