| Project title |
Porous decellularized hypertrophic tissue engineered cartilage as a scaffold for large bone defect healing |
| Summary |
Most bones develop by endochondral ossification, the replacement of hypertrophic cartilaginous templates with bone. It has recently been demonstrated that adult human bone marrow derived mesenchymal stem cells (MSCs) can be used to engineer cartilaginous tissues that act as a template for bone formation in vivo21. While conceptually appealing as a treatment option for bone regeneration, clinical translation of any cell-based therapy is hampered by high costs and significant regulatory challenges. The hypothesis of this proposal is that a porous scaffold derived from decellularized hypertrophic cartilage engineered using allogenic bone marrow derived MSCs will be highly osteoinductive, support vascularisation, allow osteoclastic resorption and will promote bone formation by host progenitor cells. This scaffold will be compared to a highly porous collagen-hydroxyapatite scaffold which has been designed specifically for bone repair. The scaffold will be evaluated by demonstrating its ability to induce ectopic bone formation in a subcutaneous nude mouse model. If proven effective, such a treatment option would provide an off-the-shelf solution for the treatment of large bone defects. |
| Funding Agency |
AO Foundation |
| Programme |
Large Bone Defect Healing |
| Type of Project |
|
| Date from |
01/01/2012 |
| Date to |
31/12/2013 |
| Person Months |
24 |
|
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| Project title |
Novel mesenchymal stem cell based therapies for articular cartilage repair |
| Summary |
Once damaged articular cartilage has a limited reparative capacity and thus lesions often progress to arthritis. This has motivated the development of cell based therapies for the repair of cartilage defects such as autologous chondrocyte implantation (ACI). Such therapies are limited in two ways. Firstly, they do not result in the regeneration of hyaline cartilage and hence the repair is temporary. Secondly, widespread adaptation into the clinical setting is impeded by practical issues such as the high cost and time required for culture expansion of chondrocytes. The applicant is of the belief that both issues cannot currently be addressed by a single new therapy. Therefore the proposed project will put forward separate solutions to both issues. The first theme of the project will determine whether freshly isolated (not culture expanded) infrapatellar fat pad derived cells, embedded in a hydrogel containing microbead-encapsulated growth factors, can used to engineer functional cartilage tissue. A component of this theme will involve magnetic microbead selection for cells with surface markers associated with mesenchymal stem cells (MSCs). Theme 2 of the proposed project will explore an alternative therapy for cartilage defect repair. Specifically, the objective is to tissue engineer in vitro a functional tissue with a zonal structure mimicking that of normal articular cartilage using MSCs. It is hypothesised that such a zonal structure can be generated by controlling the oxygen tension and mechanical environment within the developing tissue. The final theme of the project will be to determine if repairing high-load bearing cartilage defects using such tissue engineered grafts will result in significantly improved repair compared to ACI. |
| Funding Agency |
European Research Council |
| Programme |
Starter Award |
| Type of Project |
|
| Date from |
2010 |
| Date to |
2015 |
| Person Months |
60 |
|
|
| Project title |
Mechanobiology of mesenchymal stem cells for articular cartilage repair |
| Summary |
Mesenchymal stem cells (MSCs) have the ability to differentiate into distinctive end-stage cell types, such as those that synthesise specific mesenchymal tissues including cartilage, bone, tendon and muscle. MSCs have a number of advantages over primary chondrocytes for cartilage repair, including their ease of expansion and maintenance of phenotype. It has been shown that MSCs isolated from patients with knee OA show greater chondrogenic capability than primary chondrocytes obtained from articular cartilage biopsies from the same OA joints. However the clinical use of MSCs is restricted by insufficient knowledge of how the environment such cells will experience in vivo will influence the long-term stability of the repair tissue. The objective of this research is to provide a better understanding of how the mechanical loading experienced by MSCs or engineered tissues in vivo will influence their differentiation pathway and the quality and type of tissue they produce. Furthermore we wish to investigate whether the mechanical properties of scaffolds used to provide functional support to implanted cells can be optimised to promote and enhance chondrogenesis of the repair tissue. |
| Funding Agency |
Science Foundation Ireland |
| Programme |
President of Ireland Young Researcher Award |
| Type of Project |
|
| Date from |
2008 |
| Date to |
2013 |
| Person Months |
|
|
|
| Project title |
A new constitutive framework to investigate the role of mechanical forces on protein synthesis and organization during differentiation of mesenchymal progenitor cells |
| Summary |
It is believed that the mechanical environment of mesenchymal stem cells can influence their differentiation pathway. A number of different hypotheses have been proposed which describe how mechanical forces can regulate this pathway. It has been possible to test many of these ideas by encapsulating the hypothesis into an algorithm, and then conducting ‘numerical experiments’ to determine if the hypotheses on which the algorithm is based can predict realistic patterns of tissue differentiation. It is still unclear as to how the mechanical properties of tissues change during the differentiation process due to changes in protein synthesis, assembly, cross-linking, orientation etc. The hypothesis under investigation here is that mechanical forces regulate protein synthesis and organization during the differentiation of cells of the mesenchymal lineage, and hence the resulting mechanical properties of the differentiating tissue. |
| Funding Agency |
IRCSET |
| Programme |
|
| Type of Project |
|
| Date from |
2008 |
| Date to |
2012 |
| Person Months |
|
|
|
| Project title |
Design and development of a novel device to control the fabrication, confined compression and in situ delivery of cell-seeded collagen gel scaffolds |
| Summary |
Tissue engineering strategies offer a potential solution for cartilage defect repair, however results to date have been mixed. Delivering a functional cell-seeded construct to the defect site would appear to be critical for successful cartilage repair. Recently it has been shown that plastic compression of collagen gel scaffolds leads to significant increase in the mechanical properties of the scaffold. The objective of this project is to develop a hand-held clinical device to control the gelation and levels of confined compression applied to cell-seeded collagen gels prior to implantation. By controlling the rate and magnitude of the confined compression, it is hypothesised that a gradient scaffold with depth dependant mechanical properties similar to normal articular cartilage can be fabricated and delivered directly to the defect site |
| Funding Agency |
Enterprise Ireland |
| Programme |
Proof-of-Concept |
| Type of Project |
|
| Date from |
2008 |
| Date to |
2009 |
| Person Months |
|
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| More Research Projects>>> |
Steward AJ, Wagner DR, Kelly DJ, The pericellular environment regulates cytoskeletal development and the differentiation of mesenchymal stem cells and determines their response to hydrostatic pressure., European cells & materials, 25, 2013, p167-178
Url |
Nagel, T., Kelly, D.J. , The Composition of Engineered Cartilage at the Time of Implantation Determines the Likelihood of Regenerating Tissue with a Normal Collagen Architecture., Tissue Engineering Part A, 2013, p0-0
DOI |
Haugh, M.G., Thorpe, S.D., Vinardell, T., Duffy, G.P. and Kelly, D.J. , The application of plastic compression to modulate fibrin hydrogel mechanical properties., Journal of the Mechanical Behavior of Biomedical Materials, 16, 2012, p66-72
DOI |
Kasiri, S., Kelly, D.J. Taylor, D. , Can The Theory of Critical Distances Predict the Failure of Shape Memory Alloys?, Computer Methods in Biomechanics and Biomedical Engineering , 14, (6), 2011, p491-496
Notes: [PMID: 21331959 ]
DOI |
Haugh, M.G., Meyer, E.G., Thorpe, S.D., Vinardell, T., Duffy, G.P. and Kelly, D.J., Temporal and Spatial Changes in Cartilage-Matrix Specific Gene Expression in Mesenchymal Stem Cells in Response to Dynamic Compression., Tissue Engineering Part A , 23-24, 2011, p3085-3093
DOI |
| More Publications>>> |
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Last Updated:25-MAY-2013 |