Harnessing clay nano-particles for stem-cell driven tissue regeneration

Gels made from clay could provide an environment able to stimulate stem-cells due to their ability to bind biological molecules.

That molecules stick to clay has been known by scientists since the 1960s. Doctors observed that absorption into the blood stream of certain drugs was severely reduced when patients were also receiving clay-based antacid or anti-diarrhoeal treatments. This curious phenomenon was realized to be due to binding of the drugs by clay particles. This interaction is now routinely harnessed in the design of tablets to carefully control the release and action of a drug.

Dr Dawson now proposes to use this property of clay to create micro-environments that could stimulate stem cells to regenerate damaged tissues such as bone, skin, heart, spinal cord, liver, pancreas and cornea.

The rich electrostatic properties of nano (1 millionth of a millimetre) -scale clay particles which mediate these interactions could allow two hurdles facing the development of stem-cell based regenerative therapies to be overcome simultaneously.

The first challenge - to deliver and hold stem cells at the right location in the body - is met by the ability of clays to self-organise into gels via the electrostatic interactions of the particles with each other. Cells mixed with a low concentration (less than 4%) of clay particles can be injected into the body and held in the right place by the gel, eliminating, in many situations, the need for surgery.

Clay particles can also interact with large structural molecules (polymers) which are frequently used in the development of materials (or 'scaffolds'), designed to host stem cells. These interactions can greatly improve the strength of such structures and could be applied to preserve their stability at the site of injury until regeneration is complete.

While several gels and scaffold materials have been designed to deliver and hold stem cells at the site of regeneration, the ability of clay nanoparticles to overcome a second critical hurdle facing stem-cell therapy is what makes them especially exciting.

Essential to directing the activity of stem-cells is the carefully controlled provision of key biological signalling molecules. However, the open structures of conventional scaffolds or gels, while essential for the diffusion of nutrients to the cells, means their ability to hold the signalling molecules in the same location as the cells is limited. The ability of clay nano-particles to bind biological molecules presents a unique opportunity to create local environments at a site of injury or disease that can stimulate and control stem-cell driven repair.

Dr Dawson's early studies investigated the ability of clay gels to stimulate the growth of new blood vessels by incorporating a key molecular signal that stimulates this process, vascular endothelial growth factor (VEGF). In a manner reminiscent of the observations made in the 60s, Dr Dawson and colleagues observed that adding a drop of clay gel to a solution containing VEGF caused, after a few hours, the disappearance of VEGF from the solution as it became bound to the gel. When placed in an experimental injury model, the gel-bound VEGF stimulated a cluster of new blood vessels to form.

These exciting results indicate the potential of clay nanoparticles to create tailor-made micro-environments to foster stem cell regeneration. Dr Dawson is developing this approach as a means of first exploring the biological signals necessary to successfully control stem cell behaviour for regeneration and then, using the same approach, to provide stem cells with these signals to stimulate regeneration in the body.

The project will seek to test this approach to regenerate bone lost to cancer or hip replacement failure. If successful the same technology may be applied to harness stem cells for the treatment of a whole host of different scenarios, from burn victims to those suffering with diabetes or Parkinson's.

By 2033 23% of the UK population will be aged over 65. With this increase the already substantial socio-economic cost incurred by inadequate bone/ cartilage reconstructive techniques will increase dramatically. Fractures alone currently cost the European economy 17 billion euros and the US economy $20 billion annually. Worldwide, over 4 million bone replacement procedures are carried out each year, 90% of which rely on either the painful and source-restricted transplantation of the patient's own bone, or else, cadaveric bone matrix which provides only temporary structural support. By proposing a novel translatable approach to harnessing stem cells for skeletal regeneration this research program has potential to impact this unmet need and improve quality of life.

The direct beneficiaries of this work will be orthopaedic, spine and maxillofacial patients and related healthcare staff for whom current reparative options have proved inadequate. Additional beneficiaries will include the UK tax payer through reducing cost of, for example, revision surgery, and UK industry by feeding the private biomedical technology sector. In the long-term, the implications of this proposal have considerably broader regenerative applications extending the list of potential beneficiaries to include burn victims, sufferers of Parkinson's and diabetes, as well as transplant patients - all with associated broader socio-economic benefits. Educational benefit will also be sought through the development of a high-quality public engagement programme, and by investing in young research talent.

As an example of an application promising near-term socio-economic benefit, I present proof-of-concept that clay particle coating of cadaveric bone matrix can hold a potent bone inducing molecule to its surface. This could enhance the efficacy of a widely used intervention for bone reconstructive surgery. I am currently working with University of Southampton Research and Innovation Services (RIS) to patent this approach. In years 1-2 I will explore with RIS and the Medical Technologies Innovation and Knowledge Centre in Leeds to explore commercialisation routes (licensing or spin out) for this technology. The University of Southampton has a particularly successful record of commercial translation with a direct annual income of £500,000 from licensing and the launch of 12 spin-outs, since 2001, with a current market value of circa £150M.

In years 3-5 I will intensively pursue collaborations with disease-focussed research and industry to target both long and near-term beneficiaries beyond skeletal applications. For example, I recently received as co-applicant, 'Adventures in Research' pilot funding in collaboration with Dr Nicholas Evans, University of Southampton, seeking to apply clay gels for enhancing regeneration in ulcerative skin conditions such as diabetic foot ulcers.

As well as direct socioeconomic impact, the proposal will benefit emerging research talent within the University of Southampton through immersing graduate students and a postdoctoral researcher (PDRA) in a rigorous multidisciplinary research program. Beyond academic development, I will involve the PDRA in public engagement (below) and in the exploration of translational pathways.

I recognise that continued public engagement around the themes of stem cells and regenerative medicine is vital to maintain public confidence and strengthen the case for investment. I am a passionate communicator of science and value the opportunities that active involvement in regenerative research presents to engage in discussions around this hot-topic. I have requested £35k to allow me to develop, in the first year, an interactive teaching aid with public engagement specialists to feature in the "Bringing Research to Life Roadshow". This will extend and enhance the educational impact of this programme throughout the time frame of the grant, and beyond, to a broad public audience.