Periodic Reporting for period 2 - MEMETic (Mechanobiologically mimetic model systems for study of Bone disease (MEMETic))
Periodo di rendicontazione: 2022-03-01 al 2023-08-31
Despite immense efforts to develop therapies for osteoporosis, conventional drugs that target bone loss only prevent osteoporotic fractures in 50% of sufferers, and the worldwide economic burden of treatment is projected to reach $132 billion by 2050. Our research has (1) identified important tissue-level changes in osteoporotic bone and (2) provided evidence that the biological mechanisms by which bone cells normally respond to their mechanical environment are impaired. This MEMETic proejct builds upon our important research findings and strives to significantly advance the state of the art in the field of mechanobiology to understand osteoporosis aetiology and ultimately inform effective therapies.
A particular challenge for the international research field, has been that most current understanding of bone mechanobiology and pathophysiology has been derived either using 2D cell culture, which fails to capture vital biomechanical aspects of bone that govern bone biology, or animal studies, whose biology differs from that of humans. So, existing approaches cannot fully capture, or account for both human biological and mechanical factors, and this project seeks to address this challenge.
The global objective of the MEMETic project is to provide a paradigm change for studies of bone disease and therapeutics by consolidating, and significantly advancing, our novel approaches to develop advanced ex vivo models that recreate in vivo biomechanical cues in a living and multicellular 3D environment to replicate the mechanobiological function of bone. The MEMETic models are applied to advance understanding of osteoporosis and a new osteoporosis therapy (sclerostin antibody). A unique multidisciplinary approach, combining cell and molecular biology with biomechanical and mechanobiological techniques, is enabling these important advances, and consolidating a world leading mechanobiology research program.
A particular challenge for the international research field, has been that most current understanding of bone mechanobiology and pathophysiology has been derived either using 2D cell culture, which fails to capture vital biomechanical aspects of bone that govern bone biology, or animal studies, whose biology differs from that of humans. So, existing approaches cannot fully capture, or account for both human biological and mechanical factors, and this project seeks to address this challenge.
The global objective of the MEMETic project is to provide a paradigm change for studies of bone disease and therapeutics by consolidating, and significantly advancing, our novel approaches to develop advanced ex vivo models that recreate in vivo biomechanical cues in a living and multicellular 3D environment to replicate the mechanobiological function of bone. The MEMETic models are applied to advance understanding of osteoporosis and a new osteoporosis therapy (sclerostin antibody). A unique multidisciplinary approach, combining cell and molecular biology with biomechanical and mechanobiological techniques, is enabling these important advances, and consolidating a world leading mechanobiology research program.
The MEMETic project has developed advanced ex-vivo models that recreate the complex biological and physical environment of bone tissue. We first focused on establishing a model with mutlitple bone cells and vascular cells and grew these together to recreate how these cells interact within the body, and in that way encourage them to develop of bone-like tissues. We also grew these cells within systems known as bioreactors, that could recreate the mechanical environment that exists within bone tissue due to daily physical activity. We conducted a range of engineering and biology studies to investigate whether the tissues we developed were biologically, chemically and mechanically like mature bone tissue. We have been comparing these tissues that were grown in the laboratory to human and animal healthy and osteoporotic bone tissue, to understand how well our model tissues can represent bone tissue grown within the human body. We are developing these models to study how an osteoporosis therapy influences bone cells, with a particular focus on the timing and dosage that the therapy is administered to understand whether alternative approaches would be effective for preventing osteoporotic fracture. We have presented this research at national and international conferences, through journal publications and are currently preparing a number of journal articles for publication. This research has been awarded prizes and invited to be presented at prestigious international conferences.
We are providing novel approaches that go significantly beyond the state of the art, by: (1) emulating in-vivo biophysical cues (matrix stiffness and exogenous stimulation) to enhance mineral deposition and ensure the mechanical environment is accounted for, (2) implementing a multicellular approach enabling paracrine signalling between bone and vascular cells, (3) investigating the role of the physical activity and forces experience by bone cells in the development of osteoporosis, and (4) providing an advanced understanding of a therapy for osteoporosis. This project is challenging and unconventional as it incorporates a multidisciplinary framework across engineering and biological sciences, combining cell and molecular biology, mechanobiology and biomechanics.