People
Dr Sotirios A Korossis
Institute of Medical and Biological Engineering
School of Mechanical Engineering,
The University of Leeds,
LS2 9JT, UK.
Tel: [+44] (0)113 343 2160, Fax: [+44] (0)113 242 4611
E-mail: s.korossis@leeds.ac.uk, Room: 346
Position: EPSRC Advanced Research Fellow
Guided functional re-engineering of the mitral valve
EPSRC Advanced Research Fellowship
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 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.
Tissue Engineering of Rodent Optic Nerves as a Model for Myelination
MRC
The development and proper functioning of the human central nervous requires insulation for long nerve fibres called axons. In many ways this is similar to the insulation required to make electrical wires function correctly. A special type of cell called an oligodendrocyte is responsible for providing this insulation in the form of a substance we call myelin. There are a number of diseases where the myelin either does not form correctly, such as cerebral palsy, or where myelin breaks down later in life, such as multiple sclerosis. Individuals suffering from dismyelination experience a wide range of symptoms such as compromised motor function as well as problems with speech, learning, memory and loss of cognitive function. If the causes of these diseases and the loss of myelin are to be identified scientists require model systems that allow them to experiment with developing oligodendrocytes and thereby identify the key factors that affect them. Myelination is a complex process that cannot be modelled using unicellular culture of oligodendrocytes and the production of myelinating cell cultures is difficult, time consuming and still does not truly model myelination as it occurs in vivo. The aim of this project, which is held in collaboration with Dr. M G Salter of the Faculty Biological Sciences, is to create a unique culturing system designed to model white matter development in a way that is amenable to genetic modification and scientific study. The development of such a system will allow to successfully culture an optic nerve from the pre-myelinating stage through myelination to a point where it is fully myelinated and will be available as an experimental model for both myelination and injury. The technology developed will be used as the basis for future applications for funding that look to investigate the effect of re-perfusion following ischemic challenge, the effect of ablation of developmental proteins involved in myelination and for morphological investigation of the process of myelination. By using tissue engineering to develop a more functionally relevant model system we will be providing a proof of principal for others working on complex tissue types, who are currently using simplified mono-cellular culture systems as models.
Functional maturation of tissue In vitro in response to biomechanical stimulation
BBSRC
Supervisor: Professor Eileen Ingham, Professor John Fisher, Professor Jenny Southgate (York)
Two potential obstacles to the creation of implantable tissue-engineered tissues are inadequate mechanical properties, and lack of remodeling and growth potential. A promising tissue engineering strategy is to grow a complete three-dimensional tissue in vitro and then implant it once it has reached "maturity." The approach makes use of appropriate in vitro-propagated and -manipulated autologous stromal and mesenchymal stem cells to cellularise decellularised urinary bladder scaffolds, coupled with physically appropriate conditioning in bioreactors. This project will investigate whether smooth muscle, urothelial and mesenchymal stem cells can be guided with appropriate targeted mechanical stimuli to selectively develop in the laboratory to regenerate urinary bladder patches with appropriate biological and biomechanical functionality. The project focuses on the development of an in vitro cell culture system that will provide physiological biaxial strain fields to developing urinary bladder constructs. The purpose of the bioreactor will be the physical conditioning of the reconstituted bladder patches to provide appropriate biomechanical function prior to transplantation. The system will be designed to: (a) establish spatially uniform three-dimensional cell distributions on decellularised bladder scaffolds; (b) maintain desired concentrations of gases and nutrients in the culture medium; (c) expose developing tissue to appropriate physical stimuli simulating the slow filing and abrupt voiding of the urinary bladder.
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