Angioscaff takes forward a new generation of biomaterials to in vivo experimentation.
Lausanne (Switzerland)- Angioscaff is a major collaboration initiative funded by the 7th framework programme of the European Commission. Coordinated by Professor Jeffrey Hubbell from the Ecole Polytechnique de Lausanne, the partnership brings together more than 30 groups from leading European and Israeli academic centers, small industries and large pharmaceutical companies. Nature has provided us with an exceptional mechanism of wound healing and repair after injury. Healing starts with the formation of a fibrinogen blood clot acting as a support for re-building a new functional tissue. However there are two major problems associated with this natural scarring process. The first one is that the standard blood clot dissolves too rapidly, giving too little time for the normal repair process to take place and allowing connective, dysfunctional tissue to invade the site of injury. The second problem is the excess of inflammation that can occur in response to the injury. Angioscaff is developing radical new scaffolds, biomaterials and tissue engineering strategies for the regeneration of bone, skin, skeletal muscle, the cardiovascular, peripheral vascular and central nervous systems. Now at its halfway point, the collaboration has resulted in major advances in the early stage development of regenerative therapeutics. One of the main objectives of Angioscaff is to develop novel biomaterials. This year, the group of Kevin Shakesheff (University of Nottingham) reports the production of a second-generation scaffold for bone application. It combines CaP glass fibres and PLGA/PEG particles and is now being optimized for treating craniofacial defects and for promoting blood vessel formation. Additionally, the development of new biomaterials by Angioscaff extends to the generation of growth factor containing scaffolds. Martin Ehrbar’s team (Universitaet Zuerich) has succeeded in incorporating ephrin mimetic peptides into fibrin gels, thus providing cells with a gradient of stimulating peptides. They further developed of a strategy to cluster these peptides using star shaped PEGs before presenting them to the cells in 2D or 3D cultures, which are more efficient at transmitting the correct signals. Angioscaff also aims to validate biomaterials specifically able to promote blood and lymphatic vessel formation (angiogenesis and lymphangiogenesis). Melody Swartz’s group have developed a fibrin binding form of VEGF-C, one of the major lymphangiogenic growth factors, which also contains engineered characteristics that allows for a slow and cell-initiated release. Her group found that this engineered form of VEGF-C led to faster and more functional lymphatic capillary morphogenesis than that induced by the wild-type form of VEGF-C. The lab of Elisabetta Dejana has made a step towards the validation of Zebrafish as a model to test biomaterials. Transgenic fish models where endothelial cells are expressing GFP under an endothelial specific promoter are already available to study vascular development in the larvae. The group has performed a surgical implant of fibrin in such transgenic fish models and showed they could follow newly formed vessels with green fluorescence within the gel. The team further improved technology by using a Casper transgenic fish, which has a more transparent skin, making the fluorescent vessels more visible. This model will allow rapid and minimally invasive tests to screen biomaterials before moving to larger animals. As part of the ongoing collaborative efforts in the field of bone regeneration, the Group of Erella Livne (Technion Israel Institute of Technology) has screened various Scaffolds developed in Angioscaff for their ability to regenerate bone, when these scaffold were combined with the bone growth factor BMP-2. The various scaffolds were transplanted in subcutaneous and cranial defects in mice and each material was tested for stimulating bone regeneration. All the biomaterials tested resulted in an improvement of the regeneration capacities when they had BMP-2 incorporated when compared to the biomaterial alone. A major breakthrough in this years Angioscaff work has been the generation of materials for skin regeneration and wound healing where the biomaterial is also used as a matrix for diffusing growth factors. One such example, developed by Jeff Hubell’s lab, is PEG-fibrinogen hydrogel, engineered with a small fragment capable of binding specifically to any growth factor. The advantage of having a growth factor attached to the biomaterial is that it is released as the material is degraded, improving greatly the vascularisation of the newly formed tissue, and ultimately increasing its quality. The group of Sabine Eming (University of Cologne) further generated a bi-functional protein containing two fragments able to trigger two distinct and synergistic signaling pathways. The protein was incorporated into a fibrin matrix and tested for its ability to regenerate skin in a wound of a diabetic mice model. The results obtained were remarkable and the speed of wound healing was accelerated when compared to a control of fibrin. Histologic analysis also showed that this combination allowed an improved blood vessel growth in the healing wound. In the area of muscle regeneration, the teams of Giulio Cossu (Fondazione San Raffaele, Milan) and Dror Seliktar (Technion) have tested the muscle regenerative capacity of muscle stem cells called mesoangioblasts when they are used in combination with various biomaterials. They have shown that mesoangioblasts were able to form oriented, aligned and cylindrical myofibers when cultured in combination with a PEG Fibrinogen hydrogel. Not only the myofibers formed a well-structured muscle but they also displayed functional characteristics. When mesoangioblasts and PEG fibrinogen were injected together into the leg muscle of a mouse model of muscle injury, an increased survival of transplanted cells and a remarkable overall improvement of cell engraftment was observed, paving the way for turning stem cells into first line therapeutics. Finally, Angioscaff aims at developing imaging techniques able to monitor tissues in regeneration. Jeronimo Blanco’s group (Barcelona) has established a bi-functional, non invasive bioluminescence imaging platform able to quantify changes in gene expression and to analyse cell behaviour in materials implated in live animals thus reducing their suffering. In collaboration with the group of Jeronimo Blanco, Jons Hilborn (University of Uppsala) has developed new hyaluronan (HA)-modified hydrogels with guanidinium residues for gene delivery applications, allowing the formation of stable complexes with DNA. When complexed with a DNA plasmid expressing a fluorescent marker and injected into a mouse muscle efficient and stable DNA delivery was observed. The collaborative interactions taking place in the Angioscaff consortium allow merging unique and complementary expertise in the field of regenerative medicine, which will have a major impact on science and on society. This is best illustrated by the need for organ transplantation: 25% of patients waiting for an organ donor die before one can be found and in 2001, there were only 12607 available donors to help 81 528 patients in need. Stimulating tissue repair before organ failure will therefore permit alternative therapeutic strategies to be applied while the need for regenerative therapies is best illustrated by the increase in the aging population and the degenerative diseases associated with them.
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