Percutaneous cell delivery into the heart using hydrogels polymerizing in situ.

Heart disease is the leading cause of death in the US. Following an acute myocardial infarction, a fibrous, noncontractile scar develops, and results in congestive heart failure in more than 500,000 patients in the US each year. Muscle regeneration and the induction of new vascular growth to treat ischemic disorders of the heart can have significant therapeutic implications. Early studies in patients with chronic ischemic systolic left ventricular dysfunction (SLVD) using skeletal myoblasts or bone marrow-derived cells report improvement in left ventricular ejection function (LVEF) and clinical status, without notable safety issues. Nonetheless, the efficacy of cell transfer for cardiovascular disease is not established, in part due to a lack of control over cell retention, survival, and function following delivery. We studied the use of biocompatible hydrogels polymerizable in situ as a cell delivery vehicle, to improve cell retention, survival, and function following delivery into the ischemic myocardium. The study was conducted using human bone marrow-derived mesenchymal stem cells and fibrin glue, but the methods are applicable to any human stem cells (adult or embryonic) and a wide range of hydrogels. We first evaluated the utility of several commercially available percutaneous catheters for delivery of viscous cell/hydrogel suspensions. Next we characterized the polymerization kinetics of fibrin glue solutions to define the ranges of concentrations compatible with catheter delivery. We then demonstrate the in vivo effectiveness of this preparation and its ability to increase cell retention and survival in a nude rat model of myocardial infarction.

Engineered microenvironments for human stem cells.

Regulation of cell differentiation and assembly remains a fundamental question in developmental biology. During development, tissues emerge from coordinated sequences of the renewal, differentiation, and assembly of stem cells. Likewise, regeneration of an adult tissue is driven by the migration and differentiation of repair cells. The fields of stem cells and regenerative medicine are starting to realize how important is the entire context of the cell environment, with the presence of other cells, three-dimensional matrices, and sequences of molecular and physical morphogens. The premise is that to unlock the full potential of stem cells, at least some aspects of the dynamic environments normally present in vivo need to be reconstructed in experimental systems used in vitro. We review here some recent work that utilized engineered environments for guiding the embryonic and adult human stem cells, and focus on vasculogenesis as a critical and universally important aspect of tissue development and regeneration. Birth Defects Research (Part C) 84:335-347, 2008. (c) 2008 Wiley-Liss, Inc.

Challenges in cardiac tissue engineering.

Cardiac tissue engineering aims to create functional tissue constructs that can reestablish the structure and function of injured myocardium. Engineered constructs can also serve as high-fidelity models for studies of cardiac development and disease. In a general case, the biological potential of the cell-the actual "tissue engineer"-is mobilized by providing highly controllable three-dimensional environments that can mediate cell differentiation and functional assembly. For cardiac regeneration, some of the key requirements that need to be met are the selection of a human cell source, establishment of cardiac tissue matrix, electromechanical cell coupling, robust and stable contractile function, and functional vascularization. We review here the potential and challenges of cardiac tissue engineering for developing therapies that could prevent or reverse heart failure.