Platform Grant: Multiscale Mechanobiology for Tissue Engineering

Lead Research Organisation: Queen Mary, University of London
Department Name: Sch of Engineering and Materials Science

Abstract

Many tissues in our bodies, such as cartilage, tendon and ligaments are loaded as we move around and the living cells in the tissues are able to detect the loading and alter their activity in response. This process is called mechanotransduction and is important as it keeps the tissues healthy and functioning properly. Damage to cartilage, tendon and ligaments can occurs as a result of injury or through diseases such as arthritis, resulting in pain and loss of function. In many cases the tissues are not able to repair well following damage, causing chronic pain. Until recently the only option for these patients may be a total joint replacement. This is not good solution for younger patients as most joint replacements will only last for 10-15 years before they need to be replaced. Over the past 15 years many groups worldwide have been developing an alternative solution, involving a process know as tissue engineering. Tissue engineering typically involves the creation of a new, functioning tissue in the laboratory, using the patient's own cells and a biomaterial scaffold. The new tissue can be implanted into the patient to repair the damage. As the new tissue will be loaded when implanted back into the patient is very important to understand how loading will affect the activity of the cells. Ideally the cells should respond to the load in a beneficial manner, so that normal exercise and activity improves the repair. In fact it may be beneficial to load the tissue in the laboratory before implantation, using devices known as bioreactors. Mechanotransduction is very complex and not well understood and so more research is needed to understand the process and ultimately to improve tissue engineering-based tissue repair.At Queen Mary University of London we have been studying with the ultimate aim of developing better tissue engineering-based repair systems for cartilage, tendons and ligaments for over 15 years. Our laboratory facilities are very good and we have brought together a team of researchers from many different backgrounds, including engineers, materials scientists, biologists and orthopaedic surgeons. In that time we have developed and we have achieved funding for many individual research projects that have been very successful. The Platform Grant will allow us to develop our research further and underpin our current activity. The funding will ensure that we can retain key members of our research group and perform high-risk pilot studies to improve our chance to gaining funding. We will also be able to improve our collaborative links with the leading groups world-wide who are involved in this type of research.

Publications

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Akanji OO (2010) Dynamic compression alters NFkappaB activation and IkappaB-alpha expression in IL-1beta-stimulated chondrocyte/agarose constructs. in Inflammation research : official journal of the European Histamine Research Society ... [et al.]

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Bader DL (2008) Biomechanical analysis of structural deformation in living cells. in Medical & biological engineering & computing

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Bonzani IC (2012) Dynamic compressive strain influences chondrogenic gene expression in human periosteal cells: a case study. in Journal of the mechanical behavior of biomedical materials

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Campbell JJ (2008) Mechanical loading modulates intracellular calcium signaling in human mesenchymal stem cells. in Journal of applied biomaterials & biomechanics : JABB

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CHEN J (2015) FINITE ELEMENT ANALYSIS OF MECHANICAL DEFORMATION OF CHONDROCYTE TO 2D SUBSTRATE AND 3D SCAFFOLD in Journal of Mechanics in Medicine and Biology

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David Alan Lee (Author) (2012) Mechanical loading modulates intracellular calcium signaling in human mesenchymal stem cells. in Journal of applied biomaterials & biomechanics : JABB

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Garcia M (2010) Cyclic loading opens hemichannels to release ATP as part of a chondrocyte mechanotransduction pathway. in Journal of orthopaedic research : official publication of the Orthopaedic Research Society

 
Description Many tissues in our bodies, such as cartilage, tendon and ligaments are loaded as we move around and the living cells in the tissues are able to detect the loading and alter their activity in response. The study of this process is called mechanobiology and is important as loading keeps the tissues healthy and functioning properly. Damage to cartilage, tendon and ligaments can occurs as a result of injury or through diseases such as arthritis, resulting in pain and loss of function. In many cases the tissues are not able to repair well following damage, causing chronic pain. Until recently the only option for these patients may be a total joint replacement. This is not good solution for younger patients as most joint replacements will only last for 10-15 years before they need to be replaced.

Over the past 10 years or so many groups worldwide have been developing an alternative solution, involving a process know as tissue engineering. Tissue engineering typically involves the creation of a new, functioning tissue in the laboratory, using the patient's own cells and a biomaterial scaffold. The new tissue can be implanted into the patient to repair the damage. As the new tissue will be loaded when implanted back into the patient is very important to understand how loading will affect the activity of the cells. Ideally the cells should respond to the load in a beneficial manner, so that normal exercise and activity improves the repair. In fact it may be beneficial to load the tissue in the laboratory before implantation, using devices known as bioreactors.

At Queen Mary University of London we have been studying mechanobiology for over 20 years, with the ultimate aim of developing better tissue engineering-based repair systems for cartilage, tendons and ligaments. Over the past 5 years we have used the funding from the EPSRC Platform Grant to develop our research further and underpin our current activity. The funding has been used to ensure that we can retain key members of our research group and perform high-risk pilot studies to improve our chance to gaining funding. Indeed work from the Platform grant has been important in attracting follow-on funding of over £3 million. The funding has helped to develop the careers of the post-doctoral scientists involved, with two already taking full academic positions subsequently.

Research highlights include work demonstrating that communication between tendon cells, via structures called gap junctions is disrupted when the tendon is loaded. This is linked to major alterations in the expression of genes involved in maintaining the tendon tissue. We have also shown that mechanical loading affects the differentiation of stem cells, and that alterations in the organisation of the nucleus with loading may be of major importance in controlling this process. Our research has revealed that loading can act in an anti-inflammatory manner for cartilage, which may be important in controlling the progressive of osteoarthritis. In collaborative work with the University of Auckland we have suggested that a structure called the primary cilium may control this process by acting as a mechanosensor. Finally we have investigated the energy metabolism of cartilage cells and have demonstrated that the cells dramatically change their oxygen consumption when they are grown in the laboratory prior to being used in tissue engineering. Mechanisms that prevent this change may be used to improve the ability of the cells to make new cartilage tissue. The research has resulted in an impressive number of research journal publications, 36 in total.

Over the course of the grant we have run an active and diverse programme of public engagement activities. Particular highlights include development of an interactive exhibit entitled the Bionic Man and a cartilage tissue engineering interactive at the hugely popular Centre of the Cell science centre (see links below).
Exploitation Route There are a large number of different potential beneficiaries associated with this Platform Grant application as follows: Named Researchers and Others within the Host Group Beneficiaries will clearly include the named researchers as well as others within the host research group. The proposed platform grant will provide a springboard from which these researchers can develop their own independent research activity. Indeed the applicants already have a good track record in encouraging and facilitating the development of individual's scientific careers. Collaborating Research Groups The underpinning nature of the proposal will also greatly enhance the group's international and national research collaborations. The flexibility of this platform grant proposal is ideally suited to supporting high risk or pump priming collaborative multidisciplinary research. This is evidenced by the strong letters of support from potential collaborators, which have been included in the submission. Wider Scientific Community The wider scientific community will also benefit through the dissemination and transfer of expertise, particularly, that associated with some of the state-of-the-art technology such as FLIM, computational image analysis or biomechanics. To this end, we envisage that the group may host specialist technology seminars similar to previous events at which the applicants have been keynote speakers, such as the European Society of Biomechanics, Techniques Workshop (Eindhoven 2005). These workshops will be supported by the appropriate industry and will ensure direct benefit to the wider research community who may not be involved in direct collaborative activity with the applicants. In addition, the applicants anticipate that the grant will generate substantial scientific output in the form of peer reviewed journal papers. These will enhance the scientific understanding of key strategic areas of mechanobiology and its application to tissue engineering, thereby benefiting other researchers working in this area. Healthcare Industry Furthermore, the nature of this work is geared towards the future development of new patentable technology and hence beneficiaries will also include the Medical Technology, Pharmaceutical and Healthcare Industries, with possible formation of spin-out companies. Patients and the Health of the Nation Finally the key overarching aim of this research activity is to improve the quality of like of individuals suffering from debilitating diseases or injuries which, in the future, will be treated with new tissue engineering therapies based on an improved understanding of mechanobiology. Therefore, perhaps the most important beneficiaries will be the potential patients themselves and the resulting benefit to the overall health of the nation.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Over the course of the grant we have ran an active and diverse programme of public engagement activities in which we have featured some of the research taking place and tried to communicate our enthusiasm for this exciting area of science and engineering. Particular highlights include the national Big Bang Science festival in 2011 and 2012, where we ran an interactive exhibit entitled the Bionic Man. This enabled the general public to have a 'hands on' experience of different medical implants including the use of tissue engineering. The exhibit was hugely successful specifically interacting with over 1000 visitors over the course of the 3 day event and receiving excellent official visitor evaluation reports. The interactive has subsequently toured a series of other science festivals including regional Big Bangs, National Science Week, Health Summer schools, STEM schools, conferences and school events. The physical Bionic Man interactive has also been converted into a virtual interactive which now features in various European Science centres and on the Xplore health website where it has received over 5000 hits in less that 12 months (http://www.xplorehealth.eu/en/media/become-medical-engineer). The specific area of cartilage tissue engineering, on which much of the grant was focussed, has been the subject of further public engagement activity in the form of an interactive at the hugely popular Centre of the Cell science centre. This interactive supported by special outreach lectures, and youth forum events examines the science behind manipulation and culture of individual cells for cartilage tissue engineering (http://www.centreofthecell.org/interactives/bioengineering/). A further activity has seen the development of a so called 'mechanobiology virtual lab' (http://www.virtualmechanobiology.com/) in which students can learn about the practical steps involved in scientific investigation of cartilage mechanobiology. This has proved a valuable teaching aid for degree students enabling us to disseminate some of the research taking place on this EPSRC platform grant. Overall we believe our public engagement activity has been extensive and of an extremely high standard, with significant impact as recognised by positive visitor evaluations and the large numbers of people we have engaged with.
First Year Of Impact 2012
Sector Healthcare,Culture, Heritage, Museums and Collections
Impact Types Cultural,Societal

 
Description AO Research Institute
Amount £77,922 (GBP)
Funding ID S-12-15K 
Organisation AO Foundation 
Department AO Research Institute
Sector Charity/Non Profit
Country Switzerland
Start 10/2012 
End 09/2014
 
Description AO Research Institute
Amount £77,922 (GBP)
Funding ID S-12-15K 
Organisation AO Foundation 
Department AO Research Institute
Sector Charity/Non Profit
Country Switzerland
Start 10/2012 
End 09/2014