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Development of Biomaterial-based Delivery Systems for Ischemic Conditions - An Integrated Pan-European Approach

Final Report Summary - ANGIOMATTRAIN (Development of Biomaterial-based Delivery Systems for Ischemic Conditions - An Integrated Pan-European Approach)

Ischemic diseases are caused by the restriction of blood supply (lack of angiogenesis) resulting in damage or dysfunction of tissues. Ischemia occurs when blood supply to a tissue is limited, an example being ischemic heart disease, the most common cause of death in the western world from which 16 million European adults currently suffer. Ischemia is not limited to heart disease and has a wider scope across other medical conditions. Ischemia has a number of causes such as blockages, as in the case of cholesterol blockages in atherosclerosis or the clotting that may cause ischemic stroke, inflammation as in ischemic colitis, or conditions such as sickle cell anaemia. Acute limb ischemia occurs when blood supply is lost to a limb, with delayed treatment leading to morbidity, amputation and even death.

Therapeutic angiogenesis, which aims at inducing the formation of new blood vessels, involves a complex series of molecular and cellular interactions. AngioMatTrain proposes a multidisciplinary approach to achieve the design of sophisticated recombinant biomaterial carriers as therapeutic delivery systems to facilitate the controlled release of optimum doses of angiogenic factors within the microenvironment. In order to achieve this objective and fully exploit the potency of angiogenic factors for therapeutic purposes while avoiding its deleterious effects, AngioMatTrain has incorporated these fundamental principles in the design of novel biology-oriented therapeutic strategies.

AngioMatTrain focuses on the comprehensive, multidisciplinary understanding of ischemic diseases, from basics to translation, fully supported by eight full partners (five universities, one hospital and two SMEs). The programme has educated and trained twelve Early Stage Researchers and three Experienced Researchers in: tissue engineering, materials science, chemistry, functionalisation, cell biology, nanotechnology, bio-analytical techniques, preclinical models and prototype design. The researchers have undertaken cross-disciplinary and intersectorial research projects, which when combined have delivered a novel, biomaterial-based, therapeutic device for the treatment of ischemic disease. Fellows have also participated in a research training programme designed to ensure high-calibre candidates, best placed to secure employment in the private or public sector. Fellows have experienced both private and public sector research and development environments through considered secondments. The project has a public website at www.angiomattrain.eu.

The five overarching objectives of the research programme are to: 1) Synthesise and fabricate self-assembled nanoscale biomaterial systems, 2) Design delivery mechanisms for small and large biomolecules to specific sites for angiogenesis, 3) Develop functionalised self-assembled biomaterials, 4) Conduct preclinical studies on the delivery of functionalised angiogenic biomaterials and 5) Develop the delivery device. The consortium is strategically positioned to deliver the above goals.

The glycoprofile studies used by the National University of Ireland, Galway (NUIG) to evaluate the novel functionalisation technologies have allowed a deeper insight into the molecular mechanisms occurring at the different stages of the ischemia-reperfusion process in myocardial infarction and limb ischemia. These are the first ever studies that document these changes and are a significant contribution to the field of regenerative medicine. Additionally, NUIG fabricated a ROS sensitive delivery system that is able to generate oxygen to enhance the anti-inflammatory effect of the ROS responsive linking system. This development is a breakthrough technology in biomaterials therapeutic delivery platforms for inflammatory diseases.

The resulting self-assembling peptide scaffolds created by the Foundation for Research and Technology (FORTH) allow their functionalisation with signalling molecules to control cell adhesion, proliferation and differentiation. Additionally, the developed photopolymerised GelMa and methacrylated elastin-like recombinamer (ELR) hydrogels can be further developed to obtain precise control over cellular microenvironments and induce an angiogenic response to treat ischemic conditions.

The University Hospital Basel Switzerland (UHBS) developed two approaches to enhance angiogenesis in a preclinical model of limb ischemia. VEGF immobilised in the form of a gradient in an ELR hydrogel will induce more efficient and faster vascularisation in vivo compared to an equivalent factor dose homogenously distributed in the scaffold. Additionally, the developed gene-activated matrix ensures a prolonged and efficient delivery of a plasmid vector, in combination with balanced co-expression of VEGF and PDGF-BB, leading to the robust formation of normal and stable vascular networks, while avoiding aberrant angiogenesis.

Consiglio Nazionale delle Ricerche (IPCB-CNR) designed and developed a multifunctional hydrogel acting as a reservoir system to deliver specific biomolecules to targeted ischemic sites. The results contributed towards characterising the optimal hydrogel in vitro and to the design inputs for the delivery devices to treat ischemic conditions being developed by Selyno and VivaSure.

Universidad de Vallodolid (UVa) used catalyst free click-chemistry to crosslink an ELR hydrogel in order to obtain a platform for cell colonisation that is biodegraded by MMPs released by cells, which will lead to new vascular tissue formation. Additional ELRs developed by UVa contain two proteolytic target sites that degrade in response to tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA) with tunable rates. The ELRs will support angiogenesis through a combination of cell adhesion and cell induced degradation and remodelling.

University of Brighton (UoB) used hyperbranched molecules, called dendrons, as molecular scaffolds for the spatial exposure of angiogenic bioactive peptides. The peptides are capable of stimulating cells or tissues to artificially induce new vessel formation and provide an innovative and alternative method to regenerate damaged tissues. The polypeptide system was successfully integrated into the linking system developed by NUIG.

Selyno Biomedical Ltd (SYB) wrote protocols for the ELR hydrogel to be prepared, extruded, moulded and implanted in a standard operating room using a robust procedure. Standard protocols for the manufacturing of the ELR hydrogel will enable an efficient technology transfer process to a GMP subcontractor in the future.

VivaSure Medical Ltd. (VivaSure) investigated and developed a delivery device for the myocardial infarction clinical target. Relevant patient, condition, clinical treatments and other market research were collated and compiled to create a set of product design inputs. The most suitable conformity pathway for the delivery device was investigated.