Recent evidence suggests that the delivery of progenitor cells to the infarcted heart improves mechanical function, although the functional mechanism remains equivocal. A major limitation of cell delivery systems for cardiac repair has been ineffective localization and retention of cells in the heart. Recently, we developed new methods for producing biopolymer micro-threads that can be tailored to modulate cell attachment and migration. By attaching these micro-threads to a surgical needle, we have developed a novel biological suture that can be seeded with cells. This method efficiently delivers cells to the heart with a 63.6 ? 10.6 % engraftment rate, which is significantly higher than the 11.8 ? 6.2 % engraftment rate determined for intramyocardial injection. Based on these observations, we hypothesize that fibrin micro-thread-based delivery of progenitor cells can efficiently deliver cells to infarcted regions of the heart, resulting in improved mechanical function. In the first aim, we will determine how strategically enhancing cell adhesion to micro-threads with ECM proteins prior to implantation improves cell engraftment in the beating rat heart. As multiple cell types have been shown to improve mechanical function in the infarcted heart, we will investigate the delivery of two different types of cells: pre-differentiated induced pluripotent stem (iPS) cell-derived cardiomyocytes and mesenchymal stem cells (MSCs). We will also determine how extending cell incubation time increasing cell adhesion strength to micro-threads.
The second aim will determine the therapeutic effects of micro-thread-mediated progenitor cell delivery on promoting myocardial regeneration and mechanical function in the infarct zone and border zone. Cell delivery as a function of viability status of myocardial tissue will be assessed by concurrently delivering cells to healthy, infarcted and border zone tissue. Cell engraftment rates and regional mechanical function will be evaluated. Expression of cardiac specific markers will also be evaluated.
The final aim will analyze how combining progenitor cell types with endothelial progenitor cells (EPCs) increases regeneration of myocardium in the infarcted rat heart. Individual micro-threads will be seeded with EPCs and combined with micro-threads seeded with iPS cell- derived cardiomyocytes or MSCs. We will also evaluate the ability of these cells to engraft and differentiate in the rat heart. Development of this innovative technology will improve cell delivery to the heart while providing targeted delivery and concise placement of cells in the region of interest.
Cell therapy is a promising treatment option for millions of Americans suffering from myocardial infarction. However, cell therapy is limited by low cell engraftment rates. The innovative use of biological sutures for cell delivery may overcome cell engraftment issues, bringing cell therapy closer to becoming a viable therapy for many Americans.
|Grasman, Jonathan M; Pumphrey, Laura M; Dunphy, Melissa et al. (2014) Static axial stretching enhances the mechanical properties and cellular responses of fibrin microthreads. Acta Biomater 10:4367-76|
|Tao, Ze-Wei; Favreau, John T; Guyette, Jacques P et al. (2014) Delivering stem cells to the healthy heart on biological sutures: effects on regional mechanical function. J Tissue Eng Regen Med :|