Heart disease remains the number one cause of death in the developed world, in large part because there is no current therapy to replace cardiac myocytes lost to myocardial infarction. The issue of how best to achieve early vascularization in the host is the most important problem limiting the success of all engineered cardiac tissues to date. The atrial appendage is the only expendable autologous cardiac tissue that would be available in virtually every patient. As a new cell source for myocardial infarct repair, autologous atrial tissue is unique in that it has not only autologous cardiomyocytes in a three dimensional scaffold, but also an inherent and extensive capillary microvasculature. Here we will examine whether, like a split thickness skin graft, atrial tissue could be revascularized rapidly by inosculation (anastomoses between formed host and graft vessels), without requiring synthesis of a de novo microvascular network. Although we have shown that atrial myocytes implanted on the ventricle in their natural scaffold survive to at least four weeks, most myocyte loss that occurs is in the first week post implantation. Several complementary strategies designed to improve early revascularization will be explored in a subcutaneous implant model. We will mobilize omentum into the subcutaneous space to examine whether proximity to a larger arterial inflow source would accelerate or augment vascularization. Then, the potential for rotating the re-vascularized tissue to the heart, maintaining its vascular (omental) arterial supply will be explored, a clinically applicable protocol. We will examine the effect on early vascularization of providing local VEGF-165, comparing the efficacy of hydrogel delivery of VEGF-165 to direct AAV gene delivery to the atrial patch. AAV gene therapy will also be used to deliver a heat shock protein directly to the patch, designed to increase myocyte tolerance to ischemia in the period before revascularization. Finally, we will examine whether a synthesis of efficacious strategies would allow us to build a second layer of atrial cardiomyocytes in the subcutaneous bed. We have developed a new AAV vector construct for myocardial gene transfer and also an organ culture system to keep atrial wall alive for up to 2 weeks to facilitate gene delivery. The goal is to produce a living, dynamic three-dimensional cardiac structure that can be engineered in vitro and revascularized rapidly in vivo. Making use of autologous adult atrial myocardium as a living engineered tissue for myocardial infarct repair is a novel bioengineering concept that has potential for imminent clinical applicability.
| Kawamoto, Shunsuke; Flynn, Jerald P; Shi, Qun et al. (2011) Heme oxygenase-1 induction enhances cell survival and restores contractility to unvascularized three-dimensional adult cardiomyocyte grafts implanted in vivo. Tissue Eng Part A 17:1605-14 |
| Thornton, J Daryl; Curtis, J Randall; Allen, Margaret D (2010) Primary care physicians' attitudes and practices regarding discussing organ donation with their patients. J Natl Med Assoc 102:52-8 |
