Smart materials for targeted stem cell fate and function in skeletal repair

We are now living much longer than we used to. But an unfortunate consequence of this is that as we reach later life the chances that we can become ill or injured increase dramatically. One big problem that elderly people face is illness and injury associated with the bones and joints. Diseases like osteoporosis and arthritis cause pain, cause bone fractures and lead to immobility and distress to tens of thousands of people each year, costing the taxpayer tens of millions of pounds. So new treatments that enable the skeleton to heal better are urgently required.

Often a transplant of pieces of bone taken from a healthy site on an injured or diseased person might be used to promote bone healing at an injury site (called an 'autograft'), or alternatively bone from a person who has recently died might be used (an 'allograft'). But these approaches have several weaknesses - for instance, limited tissue, poor healing or even the potential of the transmission of life-threatening diseases. We need alternative approaches to help cure the many people affected by bone disease and injury.

A potential way of overcoming these problems is to make new tissue from scratch in the lab by using artificial materials and a source of cells - such as stem cells - as building materials. Alternatively, artificial materials could be designed and developed to encourage the body to heal itself better than it would do alone. Such materials are sometimes called 'bioactive' or 'smart' materials because the chemical information in them can direct cells and tissue already present in the body to regenerate the missing tissue. In this research proposal we want to try to make a new kind of smart tissue scaffold that will improve bone healing.

To do this, we plan to design scaffolds and materials which can be implanted in the body and which contain millions of tiny hollow reservoirs of drugs or chemicals, called nanoparticles. Such nanoparticles have diameters of less than the width of a single human hair and we believe we can engineer them to have many qualities necessary for promoting the regeneration of tissue. For example, we plan to change the chemical composition of their 'shell' so that they release their drug cargo at different rates. This is very important, because tissue healing involves a series of important steps occurring at very different rates - the incorrect release of a chemical at an early stage, for instance, may stop or slow healing, whereas its release at a later stage may be very important in promoting healing. This is why it is vitally important to design scaffolds that release different compounds at different rates. Also, certain chemicals may be important for encouraging one type of cell to promote healing, but may stop other types cells from doing their correct jobs. To ensure the right chemicals are delivered to the right cells, we also plan to design particles that have markers on their surface that target them to a particular sort of cell - a bone cell for instance. We then plan to tether these chemical release packets to different types of biocompatible materials.

We will next test how effective our 'smart' scaffolds are in delivering chemicals to the correct cells at the correct times, as well as seeing how well the scaffolds function in promoting bone healing. To do this, we will tag the contents of nanoparticles with a dye and measure their release and uptake by a variety of different cells, for example bone cells or blood vessel cells. Finally we will implant scaffolds in simulated bone injuries in experimental rodents to test if they improve how fast and how well bones heal, using exciting techniques in x-ray computed tomography.

Ultimately, we want to do these experiments so that we can develop new treatments to prevent bone disease and improve bone healing in people. This project brings together an interdisciplinary team of engineers and biologists to try and achieve this goal.

Bone disease and injury are burgeoning in our ageing populations, leading to a high economic and social cost. Treatments for bone injury are often ineffective or inappropriate. Autograft may be limited in supply and causing morbidity at the donor site, whereas allogeneic material may be poorly osteoinductive or of unreliable efficacy and in some cases may act as an agent for the transmission of life-threatening infectious disease. To address these challenges, we propose to develop a new tissue replacement that augments bone formation through temporal and targeted delivery of chemical cues for bone induction.

To achieve this we will build on an existing collaboration between the universities of Edinburgh and Southampton focused on developing a new generation of biomaterials for bone regeneration. We will first engineer polymer nanoparticles which can carry a range of chemical cues (growth factors, small molecules, nucleic acids) and which degrade at controlled, predetermined rates. We will test this by examining release of fluorophores and by measuring uptake of released dyes by cells in in vitro assays. Next, we will use couple chemistries to tether such nanoparticles to the backbone of a variety of hard and soft tissue scaffolds. In this way, the scaffolds will provide an environment for cell in growth and will provide a reservoir of heterogeneous factors that are released at the appropriate times for the appropriate cell populations. Finally we will test the efficacy of such scaffolds in ex vivo models, such as the chorioallantoic membrane of the chick egg, and in in vivo small animal defect models. We take full advantage of the high-resolution CT imaging facilites available at Southampton to track drug delivery and tissue healing.

Our approach will provide a new technology for controlling - temporally and spatially - the delivery of factors from hard and soft tissue scaffolds. This will enable the controlled redevelopment of tissues following injury.

Our research project aims to bring together a multidisciplinary team to develop a new technology for improving tissue regeneration, and will have a number of academic, industrial, societal, economic and awareness impacts.

ACADEMIA
Many optional training opportunities will be available to the Research Fellows (Oreffo is Associate Dean International and Enterprise at the University of Southampton) to tie in with the aims of the RC UK, to develop entrepreneurship within the academic culture and the development of enterprise skills for researchers that will further enhance our fellows and critically, the impact of the research from this project grant. We will engage on an international basis to promote the UK as a centre of excellence in all aspects of materials science, stem cells and regenerative medicine. Our track records show evidence of impact in Japan (Joint publications, student research exchange with Kyoto University (Oreffo-Tabata); Europe (Leverhulme visiting fellowship -Oreffo to Dr de Andres Catalonia University), Middle East (Oreffo adjunct chair and joint research programmes at Stem Cell Unit, King Saud University, China /Hong Kong (Joint Stem Cell lab between Centre for Human Development, Stem cells and regeneration and Chinese University of Hong Kong) and many other linkages.

BUSINESS AND INDUSTRY
We have a number of industry links (see track record for MB and ROCO) and will communicate openly with appropriate industry partners (IP discussions will be undertaken underunder CDAs) especially towards the final phase of our programme as we develop robust strategies for growth factor delivery from our various scaffolds for tissue regeneration. See 'Pathways to Impact' for more details.

GENERAL PUBLIC - PUBLIC AWARENESS AND POLICY
We will engage with the general public to explain, sensitively (management of expectation is key in this area of research) the clinical and commercial potential of our work. We believe that stem cell biology and the life sciences - encapsulated by our project have a special responsibility to explain stem cell science, materials chemistry and bioengineering to schoolchildren. There is significant potential in this area including vast potential from a reparative standpoint for bone stem cells in orthopaedics and skeletal stem cell biology across a range of clinical areas and the importance of multidisciplinary science - our outreach programme will provide impact over the next 3 years through active schools outreach by ROCO, MB, NDE and all the applicants.

GENERAL PUBLIC - HEALTH AND WELL-BEING
TSB Cell Therapy Catapult Centre: We will engage with the Cell Therapy Catapult as appropriate especially from a stem cell clinical translation perspective in the end phase of our programme again as appropriate (preclinical and early clinical development).
Improving Public Services: Bradley and Oreffo work closely with the clinical community (see track record) including specifically the orthopaedic community (7 clinical MD/PhD trained in the last eight years and over 30 papers and 15 awards to clinical fellows) - we will look to translate our unique scaffold approaches through to the clinic in regenerative projects, programmes as appropriate including the UK Regenerative Medicine and Medical Technologies Innovation and Knowledge Centre programmes.