The aim of this proposal is to design solutions for vascular, cardiac, and pulmonary organ failure by building interactive teams of researchers focused on specific aspects of cardiopulmonary organ engineering. Our efforts will encompass three projects: a tissue engineered blood vessel, a myocardial patch, and a biohybrid lung. The assembled research teams will function as cores of expertise that address common tasks associated with all three projects. Five research cores will be established in the following areas: 1) matrix synthesis and surface modification, 2) precursor cell isolation and characterization, 3) biomechanical testing and conditioning, 4) animal model development, and 5) construct assessment. For each of the three organ projects we have design objectives (Specific Aims) that will be achieved in the five-year period of proposed work: 1) Tissue engineered blood vessel - A biological blood vessel will be developed that achieves long-term potency in the rat model and is subsequently evaluated in the porcine model. The blood vessel will be a """"""""biological equivalent"""""""" to autologous arteries from a mechanical and biofunctional perspective. During vessel development in vitro, specific mechanical training protocols that have been optimized to direct appropriate cell differentiation and expression of matrix components will be employed. 2) Myocardial patch - A process will be developed that allows the reconstruction of functional myocardium in ischemic or dysfunctional regions of the heart, This process will be characterized by the seeding of stem cells onto a bioerodible thermoplastic elastomer which has been designed to micromechanically transmit appropriate stresses to the stem cells during an in vitro seeding period and after placement within the diseased myocardium. Vascularization of this implanted construct will be achieved by surgical placement of omental tissue atop the placed myocardial patch. 3) Biohybrid lung - An oxygenator comprised of endothelialized microporous hollow fibers arranged in: plates and rotated to mix and pump the blood will serve as a biohyrid lung capable of providing gas exchange in a calf for 14 days. The hollow fibers will be surface modified to support the culture of autologous endothelial cells. The endothelial cells will act to reduce the anticoagulation requirements of the device while maintaining adequate fiber permeability. ? ?
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