Biotextiles for ligament repair using biofunctionalisation to aid regeneration

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The project will be integrated into the UKRMP Acellular approaches for therapeutic delivery Hub, a collaboration between Manchester, Nottingham, Imperial, Southampton, Keele and others.http://www.ukrmp.org.uk/hubs/Anterior cruciate ligament (ACL) ruptures are a common problem and occur mostly as a result of sports injuries. Around 200,000 ACL ruptures per year occur in the United States and it is estimated that more than 100,000 ACL repairs are performed annually in the United States.Such ruptures can subsequently lead to other, serious degenerative joint diseases and for this reason it is important to treat and tackle ACL injuries efficiently and effectively. The current gold standard for ACL repair involves the use of patellar tendon autografts; this treatment has many limitations including: donor site morbidity and more importantly the inability of the graft to fully integrate with the bone tunnel site (area often referred to as the enthesis). High failure rates often occur particularly at this enthesis site subsequently leading to patient revisits for further improved surgeries. Hence, an intervention is required which could be coupled with the current gold standard method to act as a dual technology, which could provide more robust graft integration.Some research has been performed in developing alternative grafts fabricated from synthetic FDA approved materials including Poly-e-Caprolactone (PCL) and PET with the hope to manufacture tissue-engineered grafts that would provide the required mechanical properties. However, limitations associated with such constructs include their lack of bio-interaction, lack of functional neo-matrix lay down and remodeling, leading to failure at the enthesis site. Therefore, the problem of graft failure (autograft or synthetic) at the enthesis site is yet to be fully resolved. For this reason this study aims to improve graft integration at the enthesis site through improved healing rate.In this case, we aim to develop a synthetic graft, which is able to precisely mimic the nano-and micro- architecture of native tissue ACL extracellular matrix along with the appropriate mechanical properties and degradation rate. Working in collaboration with Professor Eithne Comerford (University of Liverpool), we aim to identify key extracellular matrix (ECM) protein fragments within the different regions of the ACL (particularly the enthesis) and functionalise these onto the synthetic graft. We have identified fibrillin-1 as a starting point and preliminary results have shown significantly more rapid attachment and alignment along the electrospun fibres with fibrillin present. Further molecules have been identified and will be explored along with signalling pathways.Cell behavior will be assessed in terms of cell viability, morphology, proliferation, differentiation, intra- and extracellular signalling pathways and neo-matrix secretion. These will be validated and identified using via immunocytochemistry, ELISA, RT-PCR and histology.Additionally the electrospun system could be used as a platform technology for other ligaments and also tendon repair.