Guided Functional Re-engineering of the Mitral Valve

Lead Research Organisation: University of Leeds
Department Name: Mechanical Engineering

Abstract

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.

Publications

10 25 50

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Granados M (2017) Development and Characterization of a Porcine Mitral Valve Scaffold for Tissue Engineering. in Journal of cardiovascular translational research

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Iablonskii P (2015) Tissue-engineered mitral valve: morphology and biomechanics †. in Interactive cardiovascular and thoracic surgery

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Knight RL (2008) The use of acellular matrices for the tissue engineering of cardiac valves. in Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine

 
Description Discipline Hopping
Amount £103,628 (GBP)
Funding ID G0601737 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2007 
End 03/2008
 
Description European Commission (EC)
Amount € 3,340,211 (EUR)
Funding ID 317512 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2013 
End 12/2016
 
Description Innovation and Knowledge Centre
Amount £4,893,965 (GBP)
Funding ID EP/G032483/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 10/2014
 
Description Platform Grant
Amount £869,162 (GBP)
Funding ID EP/F043872/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 06/2008 
End 06/2013
 
Description Programme Grant
Amount £4,536,887 (GBP)
Funding ID EP/G012172/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 05/2009 
End 06/2015
 
Description Research Equipment Initiative
Amount £232,183 (GBP)
Funding ID BB/F011105/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2008 
End 07/2019
 
Description Eindhoven University of Technology 
Organisation Eindhoven University of Technology
Country Netherlands 
Sector Academic/University 
PI Contribution Coordinator of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Collaborator Contribution Partner of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Impact Joint supervision of 1 multidisciplinary PhD project. Disciplines involved: biology, engineering, physics, chemistry.
Start Year 2011
 
Description RWTH Aachen University 
Organisation RWTH Aachen University
Department Helmholtz Institute for Biomedical Engineering
Country Germany 
Sector Public 
PI Contribution Coordinator of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Collaborator Contribution Partner of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Impact Joint supervision of 1 multidisciplinary PhD project. Disciplines involved: biology, engineering, physics, chemistry, surgery
Start Year 2011
 
Description University of Padua 
Organisation University of Padova
Country Italy 
Sector Academic/University 
PI Contribution Coordinator of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Collaborator Contribution Partner of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Impact Joint supervision of 3 multidisciplinary PhD project. Disciplines involved: biology, engineering, physics, chemistry, medicine, surgery
Start Year 2011
 
Description University of Patras 
Organisation University of Patras
Country Greece 
Sector Academic/University 
PI Contribution Coordinator of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Collaborator Contribution Partner of Marie Curie Initial Training Network TECAS (Tissue Engineering Solution for Cardiovascular Surgery)
Impact Joint supervision of 3 multidisciplinary PhD project. Disciplines involved: biology, engineering, physics, chemistry
Start Year 2011
 
Company Name Tissue Regenix Group 
Description The company's patented decellularisation ('dCELL®') Technology removes DNA and other cellular material from tissue leaving intact an inert acellular matrix upon which the patients cells can repopulate. The potential applications of dCELL® are diverse and address critical clinical needs such as; wound care, heart valve replacement and knee repair. Spun out of the University of Leeds in 2006, Tissue Regenix commercialise upon research undertaken by our higher education and research partners around the world. Tissue Regenix listed on the Alternative Investment Market (AIM) on the London Stock Exchange in 2010, before opening the first subsidiary office Tissue Regenix Woundcare, Inc. in San Antonio, Texas in 2012. In early 2016, Tissue Regenix entered its first joint venture establishing GBM-V , a Tissue Bank in Rostock, Germany, granting them the first licence for the production of dCELL® heart valves, and strengthening its presence within Europe. 
Year Established 2006 
Impact The dCELL® process involves the creation of biological scaffolds which are essentially inert. By removing DNA and cellular material from biological tissues, the patient's cells can repopulate and colonize creating new, like for like tissue, which is recognized and accepted by the body, significantly reducing the risk of rejection, and stimulating a natural healing process.
Website https://www.tissueregenix.com/
 
Description Industrial Stakeholder Meetings 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact The events were focused on directly disseminating the research results to the industrial and clinical communities, which a view to the clinical translation and commercial exploitation of the research findings. Three collaborations were established as a result of these events with private companies, including Corlife oHG, LLS ROWIAK GmbH and Collplant Holdings Ltd.
Year(s) Of Engagement Activity 2013,2014,2015
 
Description Patient Focus Seminar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Patient focus seminars, delivered by academics and clinicians to selected patient groups, addressing patient priorities and concerns, and promoting TE valve therapies, interventions and technologies.
Year(s) Of Engagement Activity 2011,2013,2014,2015,2016
 
Description Primary School Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Primary School Workshops, conducted on the basis of visits to local schools. The workshops involved research-related exhibits, activities and seminars, tailored for the pupil audience.
Year(s) Of Engagement Activity 2010,2011,2013,2014
 
Description Summer School Weeks for Secondary Education Students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Summer School Weeks were organised for secondary educations students and teachers, who spent a week receiving first-hand experience from scientists, engineers and clinicians, in the form of lectures, practicals and scientific exhibits. The events also provided teachers with research-oriented ideas, resources and practices for enhancing their teaching practice.
Year(s) Of Engagement Activity 2013,2014,2015