Recent evidence suggests that the delivery of human mesenchymal stem cells (hMSCs) to the infarcted heart improves mechanical function in both clinical and experimental animal studies, although the functional mechanism remains equivocal. A major limitation of cell delivery systems for cardiac repair has been ineffective localization, persistence and retention of physiologically relevant numbers of cells in the heart. Recently, our laboratories have developed a new method of producing biopolymer microthreads that can be tailored to modulate cell attachment and migration. Further, we have demonstrated that we can precisely track the location of cells delivered to myocardium using a novel quantum dot based tracking method. Based on these observations, we hypothesize that hMSC-seeded microthreads will enhance targeted cell delivery to infarcted regions of the heart resulting in improved mechanical function. In our first specific aim, we will maximize hMSC loading onto biopolymer microthreads for delivery to the heart. We hypothesize that hMSCs seeded on biopolymer microthreads will enhance targeted cell delivery to the myocardium. Quantum dot loaded hMSCs will be incubated on fibrin microthreads. Following a period of attachment and growth on fibrin microthreads, hMSC stemness, morphology, cell density, and survival will be assessed to characterize cell quantity and phenotype in microthread delivery systems. Concurrently, we will determine the mechanical strength of these cell-seeded microthreads to assess their stability for implantation in the heart. Finally, these cell-seeded microthreads will be deployed into the beating rat heart. Cell engraftment will be assessed at 0 and 3 days post implantation. In our second specific aim, we will assess the effects of microthread-mediated hMSC delivery on left ventricular function in the infarcted rat heart in vivo. We hypothesize that microthread-mediated hMSC delivery will improve hMSC engraftment and resultant regional function in the infarcted rat heart. Cell- seeded microthreads will be delivered to the infarcted myocardium so that they span the region of the infarct and the peri-infarct border. Regional mechanical function will be assessed, along with histological evaluation of hMSC localization, survival, proliferation, engraftment, and differentiation within the infarcted heart. This microthread-based delivery system will provide effective localization of stem cells to the heart. This method will also allow scaffold-based targeted delivery, resulting in concise placement of stem cells in the region of interest. Thus, these cell-seeded microthreads serve as a platform technology for efficiently delivering viable cells to infarcted myocardium and for precisely directing cellular function.
Recent evidence suggests that the delivery of human mesenchymal stem cells to the infarcted heart improves mechanical function in both clinical and experimental animal studies. A major limitation of cell delivery systems for cardiac repair has been ineffective localization, persistence and retention of physiologically relevant numbers of cells in the heart. This proposal will overcome these limitations by developing a novel microthread based method to deliver adult stem cells to the heart.
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