Project making significant progress in biomaterial design and tissue validation
Uppsala (Sweden), October 2013. A number of encouraging advances have been made by scientists from the Biodesign consortium (www.biodesign.eu.com) and published in leading journals. This partnership is a large scale scientific collaboration coordinated by Professor Jons Hilborn (University of Uppsala, Uppsala, Sweden), and co-financed by the European Commission via the 7th Framework Programme via the grant 262948-2. It aims to design and develop state of the art therapeutic approaches for treating traumatic damage and degenerative diseases in humans and alleviate patient suffering. Progress made so far: Advances in Biomaterial design The team of R. Brown from UCL, has addressed one of the major issues in utilising collagen based biomaterials for tissue repair; the problem is that when using materials with growth factors and cells the ‘mix’ can grow out in all directions, which does not correspond to the strict alignment and positioning that occurs during tissue growth and prenecessitates that a material used for repairing tissue should provide both the structural components and a direction in which the tissue should repair to permit functional integration with the surrounding tissue. By combining compression and light dependent mixing approaches (termed: photodynamics), they have managed to create a highly structured material system, which can be tailored for multiple complex tissues. Following in similar concept, in the use of biomaterials based on naturally occurring molecules from the extra cellular matrix, the team of O. Varghese from Uppsala has developed injectable hydrogels with tunable release kinetics of therapeutic proteins based on Hyaluronic acid and glycosaminoglycans. This is a highly versatile system which can be used for the delivery of therapeutics with sustained release and as a structural backbone for guided tissue repair. In the specific context of materials for bone repair, teams from Nottingham (K. Shakesheff) and Uppsala (D. Ossipov) have created a series of biomaterials which have been tailored to treat very specific bone disorders, thereby generating real options for all possible bone disorders. Materials for bone disorders have typically focused on large bones and the skull; but such materials are not best suited for smaller bones, which has equally as important function. One such bone is that found in the ear, which needs large air spaces, not something conducive with typical bone materials that are load bearing and therefore need to be heavy and compact. The team of K. Shakesheff has tailored one of their existing materials for the development of a biodegradable scaffold tailored for ear bone air-cell regeneration. The scaffold is based on a specific particle paste, which can be molded into any size or shape and hardens into a solid scaffold at body temperature. To our knowledge, this is the first description of such a scaffold that can be pasted into a cavity and that hardens in the body for this application. The ability to paste the scaffold around the ear bone cavity offers improved clinical application and tissue approximation when compared to implants. In contrast the team of D. Ossipov from Uppsala has taken existing materials and combined them with phosphonates (which are the typical therapies of clinical bone repair in osteoporosis) to generate two new types of materials: the first generated is highly sensitive version to metal ion concentrations which has significant impact on the capacity of the material to correctly form a supportive structure while the second, the phosphonates have been combined with an extracellular matrix component, Hyaluronic acid, to generate a combination material which (i) fine tunes the release profile of growth factors loaded into the material itself, (ii) protects the growth factors from premature deactivation, and (iii) improve cell interactive properties by encouraging bone stem cells to stick better to the material itself. Advances in Tissue validation: Bone Based on the retrospective clinical analysis which revealed that the assays used during the historical development of materials for bone repair do not provide correlatory information that permit correct decision making for the development of human tissue therapeutics, the teams from the AO Foundation in Switzerland and the University of Southampton in the UK have started to identify more informative solutions to reverse this problem. As a starting point the team of M. Stoddart from Swizterland has looked at the cells themselves, which are used as the starting assays to assess if materials can induce bone generation. For the purposes of costs and ethics there is the need to use cells that do not die and do not change behaviour: termed immortalised cell lines as the starting point and then move onto cell samples obtained from humans. The issue is that unsurprisingly, samples from humans vary greatly from human to human which forces research to go around in circles as more immortalised cell lines are used to try to address the variability of human cell samples. The team from Switzerland has successfully identified two immortalised cell lines that correspond very closely to human cells, even with high variability, but more importantly suggest a paradigm shift in how all the cells are used. Instead of using one cell type as an indicator and hoping it addresses all the outcomes necessary for the next stage of development, each cell type should in fact be used exclusively for measuring effects that are specific to the cells themselves. This implies that only those materials that generate all the required positive outcomes above the required thresholds for the required effect of the material should then progress further in development. As an extension of this, and to identify lower cost, faster and more informative models for tissue repair design strategies, the team of R. Oreffo from Southampton have been searching for more ethical methods for generating living reconstructions of bone tissue. The standard approach has been uninformative cell assays, followed by extensive and very expensive animal modelling in mice, used as a screening system, which are highly variable, which when linked to the costs prevents relevant and high impact information being generated. The aim is to reduce wastage, reduce costs, have a higher ethical consideration and generate high impact therapies, as such R. Oreffo has revisited using young chicken bone cultures as the intermediary between the cell assays and the mice studies. Young chicken bones, can be surgically removed and grown in petri dishes and the effects of bone promoting repair materials tested as their differential and unique response to exogenous stimuli provides an attractive model for testing growth factors and screening therapies. And while it is considered an historical model, in fact when combined with the significant advances made in microscopy and medical imaging, it actually provides an equivalent structural insight as the mouse model, with the added advantage that the bone itself is growing in a petri dish which can be viewed over a long period of time. At present these culture tools are being assessed in the context of mechanical load to give indication of potential functionality. Thereby, by combining optimised cell screening approaches with highly informative ‘life-like’ culture systems to generate living tissue relevant information, the number of materials that are moved into animal modelling greatly decreases. Mathematically, instead of having 15 interesting materials that are screened in 60 mice at 4 mice per material to give some information, 3 very promising materials which have passed through the new assays will be assessed on 30 mice at 10 mice per material: cheaper, quicker, higher impact, more ethical information. Advances in Tissue validation: Skeletal muscle The team of G. Cossu (UCL) has been working on two interlinked avenues attempting to identify developmental signals that stimulate tissue repair, using skeletal muscle as the model tissue while simultaneously finalising the first series of preclinical experiments combining muscle stem cells with biomaterials, work that has been done in collaboration with D. Seliktar’s team (Technion). Two developmental signals and one growth factor have been identified which can have a significant impact on muscle cells in the tissue itself determining and modifying their behaviour. Developmental signals are of high interest, as these are typically only expressed in the developing embryo when the mother is pregnant and are quickly switched off as soon as the newborn starts to fend for itself. Given how quickly a baby grows, the signals provided in the growing tissue, which lay the blue print and overall structure of the tissue itself can be highly beneficial in adults. Through short term presentation or ‘turning on” of these signals, stronger and more beneficial tissue growth can be obtained, based on the stimulation of natural processes. The work was performed in mice, which as mammals share very similar developmental signaling during the growth of the baby mouse and therefore serve as critical sources of knowledge which can be leveraged to produce signals which can be combined with materials to create optimal regenerative therapeutics. In that context and in collaboration with Dror Seliktar from Technion, the closing touches have been performed for the first generation combination approaches of muscle stem cells and biomaterials to generate muscle functional restoration. Combining the two improves survival and differentiation of transplanted muscle stem cells in acute and chronic skeletal muscle degeneration. Despite being the first generation combination product, as both the cells and the material are being tested separately in clinical trials on humans, there is the potential for a rapid combination and translation to humans. Excitingly these are just the first generation approaches; optimising cell types, newer materials and more precise growth factors and developmental signals all integrated into a common therapeutic represents the future of this therapeutic avenue, and as such pioneers the new approaches being developed with BioDesign. Closing comments Professor Jons Hilborn of Uppsala and coordinator of the project stated “that these published results are the first public demonstrations of the relevance and impact of the original BioDesign project plan. We have already demonstrated the absence of correlation between clinical outputs in humans and the historical development assays used during preclinical development and are now progressing in the rational design of real regenerative therapies based upon known patient need and state of the art knowledge. Although still some way from the clinic, the foundations lain by the partners are very solid and hold great promise for the future”. Notes to editors About Biodesign Biodesign (www.biodesign.eu.com) is a partnership of 19 research and clinical teams from globally recognised academic centres, small biotech and large pharmaceutical companies working together to to generate a step-change in the science-technology strength of biomaterials research tailored to provide the means generating 21st century therapeutics which addresses a global societal need. The rational design of bio-interactive materials is critically dependent on the understanding of how relevant cells interact with natural materials as tissues form and remodel in-vivo. Through this understanding, it will then be feasible to import (adapt and apply), these natural mechanisms to synthetic biomaterials such that they operate within the ‘cell-tissue economy’, and effectively repair the tissue. Coordinated by Professor Jons Hilborn, co-financed by the European Commission via the 7th Framework Programme the aims of the project over are: • To produce a radical new approach, the ‘modular’ approach, to scaffold material synthesis/fabrication • To combine this with rapid-screening and tuning /precise/ features-to-function in biomaterials (i.e. the enabling technology). • To apply, iteratively-refine and demonstrate this new enabling technology on specific exemplars of state-of-the-art, bioinspired materials, with their European inventors. This is an outcome-driven project, comprising world-class academic and industrial participants. It will satisfy a major unmet need for the science-technology framework and produce protocols to select and tailor functional bioinspired materials an order-of-magnitude faster and cheaper. Publications referred to in this press release Mechanical anisotropy in compressed collagen produced by localized photodynamic cross-linking, Josephine P.F.Wonga Alexander J.MacRobertb Umber Cheemaa, Robert A.Brown Journal of the mechanical behavior of biomedical materials 18 (2013) 132 - 139 Mild and Efficient Strategy for Site-Selective Aldehyde Modification of Glycosaminoglycans: Tailoring Hydrogels with Tunable Release of Growth Factor. S. Wang, O. P. Oommen, Y. Han, O. P. Varghese, Biomacromolecules 2013, 14, 2427−2432. Development of a porous poly(DL-lactic acid-co-glycolic acid)-based scaffold for mastoid air-cell regeneration.Gould TW, Birchall JP, Mallick AS, Alliston T, Lustig LR, Shakesheff KM, Rahman CV. Laryngoscope. 2013 May 13. Gry Hulsart-Billström, Pik Kwan Yuen, Richard Marcell, Jöns Hilborn, Sune Larsson, Dmitri Ossipov, Bisphosphonate-linked hyaluronic acid hydrogel sequesters and enzymatically releases active bone morphogenetic protein-2 for induction of osteogenic differentiation, Biomacromolecules, 2013, 14, 3055−3063. Reza M. Nejadnik, Xia Yang, Tokio Mimura, Zeinab T. Birgani, Pamela Habibovic, Kiyoshi Itatani, John A. Jansen, Jöns Hilborn, Dmitri Ossipov, Antonios G. Mikos, Sander Leeuwenburgh, Calcium-mediated Secondary Cross-linking of Bisphosphonated Oligo(poly(ethylene glycol) Fumarate) Hydrogels, Macromolecular Bioscience, 2013, Czekanska EM, Stoddart MJ, Ralphs JR, Richards RG, Hayes JS. A phenotypic comparison of osteoblast cell lines versus human primary osteoblasts for biomaterials testing. J Biomed Mater Res A. 2013 Aug 24. [Epub ahead of print] EL Smith, JM Kanczler, ROC Oreffo (2013) A new take on an old story: chick limb organ culture for skeletal niche development and regenerative medicine evaluation, European cells and materials 2013 Volume No 26 – pages 91-106 Cappellari O, Benedetti S, Innocenzi A, Tedesco FS, Moreno-Fortuny A, Ugarte G, Lampugnanui MG, Messina G and Cossu G. 2013. Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory. Developmental Cell 24, 586-599. Fuoco C, Salvatori ML, Biondo A, Shapira-Schweitzer K, Santoleri S, Antonini S, Bernardini S, France Tedesco FS, Cannata SM, Dror Seliktar D, Cossu G, Gargioli C. 2012 Injectable PEG-fibrinogen hydrogel adjuvant improves survival and differentiation of transplanted mesoangioblasts in acute and chronic skeletal muscle degeneration. Skeletal muscle. 2(1):24.. Ugarte G, Cappellari O, Perani L, Pistocchi A, Cossu G. 2012. Noggin recruits mesoderm progenitors from the dorsal aorta to a skeletal myogenic fate. Dev Biol. 365:91-100.
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