Guided Functional Re-engineering of the Mitral Valve

The aim of this Fellowship is to research and develop tissue-engineered chordae tendineae and leaflets for mitral valve reconstruction in the heart. Mitral valve stenosis and mitral valve regurgitation are the most significant and frequent causes of valve dysfunction in the mitral position in the heart. Regardless of the nature (acquired or congenital) and underlying cause of mitral valve dysfunction, a number of common changes occur in the valve components. These include deformation, tethering, tissue thickening and/or calcification, fusion, retraction, stretching, dilatation, or rupture. Conventional therapies for mitral valve dysfunction most frequently focus on the repair or replacement of the valve. Mitral valve repair is the gold standard for mitral valve dysfunction and usually employs synthetic biomaterials or chemically treated tissue, such as pericardium, taken from donors. Both approaches only deliver inert or biocompatible material solutions that cannot regenerate or grow with the patient, and may, subsequently calcify, become rigid and eventually degenerate. Ideally, surgeons would prefer tissue taken from the patient (autologous), since it will retain viability and regenerate. In most cases, however, autologous tissue is not available, and even if it is available, this is not an ideal solution. Functional tissue engineering (FTE) is an attractive alternative, which employs scaffolds repopulated with appropriate cells taken from the indented patient, and physically conditioned in the laboratory with a view to producing viable replacement tissues with appropriate functionality prior to implantation, which will have the potential to regenerate in the patient. The intention of this multidisciplinary project is to develop and evaluate FTE simulation systems that will deliver dynamic cell culture conditions to appropriate natural tissue matrices repopulated with cells, to investigate how the biomechanical and biochemical environment can direct the development of mitral tissue-equivalents in the laboratory. The approach of this Fellowship to tissue engineering of the mitral valve involves the use of tissue matrices of both human and porcine origin that have been treated to remove the immunogenic cells, reseeded with the patient's own cells and physically conditioned in the laboratory, in order to produce biological and biomechanical functionality of the graft prior to implantation. This will create an immediate regeneration potential in response to the cyclic loading in the body. The use of decellularised-only matrices in reconstructive surgery does offer an alternative approach and will be investigated. The proposed research postulates that simulation of the type of mechanical strain that mitral tissue encounters in the body will stimulate the cells to produce tissues with similar properties in the laboratory. In particular it is hypothesised that cyclic uniaxial tensile strain will produce mitral valve chordae-equivalent tissue while biaxial cyclic strain will generate mitral valve leaflet-equivalent tissue.