Elucidating and modulating macrophage and stem cell responses to bioactive nanoclays for bone regeneration

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Medical advances have led to a welcome increase in life expectancy. However, this progress presents new challenges: increases in age-related diseases, and associated reductions in quality of life. There are over 9 million bone fractures per year, worldwide, of which approximately 5%-10% are associated with delayed healing or non-union. The field of regenerative medicine seeks new therapies that harness the potential of stem cells to regenerate damaged or diseased tissue. These therapies can involve stem cell transplantation, or using drugs and materials to recruit and stimulate stem cells already present in adult tissues.Clays offer surprisingly rich possibilities for regenerative medicine. This is largely due to their ability to adsorb and bind biological molecules; a property that has for a long time been used in the design of tablets to control the release and action of certain drugs. The UK research group have developed synthetic nano-sized (1 millionth of a millimetre) clay particles that form injectable gels that set in the body. Gelation occurs spontaneously as the clay particles bind and interlock with proteins adsorbed from blood. These protein-rich 'nanoclay gels' create environments favourable for stem cells to colonise. By mixing-in proteins called growth factors, we can recruit and stimulate stem cells to remodel the nanoclay gel into new bone tissue. Given nanoclay gels bind and do not release growth factors, these potent stem cell stimulating molecules can be used in the future to fuse bones and repair non-healing fractures with greater precision, safety and efficiency.While very promising, there is a lot about this repair process that we do not yet understand. For example, we know that the response of cells of the immune-system will play a vital role in determining how the body responds to nanoclay in the first hours and days after injection. The Japanese research group are world-leaders in understanding and controlling this immune response to implanted materials. For example the group have shown that it is possible to release drugs in a highly controlled manner at the site of repair to attract and stimulate immune cells to limit inflammation and promote regeneration. This UK-Japan collaboration will therefore study how immune cells function to clear away nanoclay particles and simultaneously attract stem cells for bone formation. In partnership, we will develop new gel technologies that combine nanoclay gels with gelatin to facilitate controlled release of a drug that influences immune cells towards regeneration. The drug we will test, pioglitazone, is already used in the treatment of diabetes and so, if successful, has a good chance of being adopted for regenerative medicine in the future. We will test our approach both 'in vitro', on cells grown in a petri dish and 'in vivo', within the body by injecting the gels under the skin of mice. In vitro experiments will employ high powered microscopes to explore the fate of clay nanoparticles after they are engulfed by the immune cells. We will also measure the biochemical signals released by immune cells in response to nanoclay and test whether cell signalling can be modified to promote regeneration by pioglitazone. 'In vivo', we will rely on state of the art live animal imaging techniques to track immune cell responses to nanoclay gels over time and correlate these responses to new bone formation via simultaneous micro CT (3D X-Ray). This exciting approach allows us to track responses in a single animal over time which substantially reduces the number of mice needed for experiments. Finally, having developed and optimised our new approach we will test the ability of the technology to accelerate bone repair in a surgically prepared bone defect in a rat cranium. These experiments are well established and essential to test our approach and justify subsequent research investment towards clinical translation for patient benefit.