Exploiting nanoclay self-assembly for stem-cell driven tissue regeneration (Ext.)

This is an extension of the Fellowship: "Harnessing clay nanoparticles for stem-cell driven tissue regeneration"

Stem cells have great potential to cure a wide variety of conditions by regenerating diseased or damaged tissue. During the body's development from an embryo and during its repair after injury, stem cells are activated by a highly co-ordinated system of signals from the local micro-environment. Intricate patterns of spatially and temporally changing concentrations of biochemical molecules direct how tissues grow and the form that they take. Being able to deliver and control these environments in the body is vital if we are to harness the potential of stem cells for healthcare.

The aim of my research is to develop a new type of hydrogel formed from nano-sized (1 millionth of a millimetre) clay particles that, when delivered into the body, provides an environment able to stimulate and direct stem cells to repair and regenerate diseased or damaged tissues such as bone, cartilage or skin.

Hydrogels are gels with a very high water content. They are excellent candidates for delivering stem cells as they allow diffusion of nutrients and their basic physical properties mimic the cell's native environment. Their major drawback is that, because they are formed mainly of water, they do not tend to allow for the precise control of biochemical signalling molecules that is so important in directing how a stem cell functions.

Certain nano-clay particles are also able to form hydrogels by forming physical interactions with each other to create a structure that locks in water. They also display the very unusual and potentially useful property of being extremely sticky for biological molecules. Over the past five years, EPSRC has funded my research exploring ways to use these properties for creating gel environments in the body that can activate stem cells to form bone. We have developed gels that can be injected into an injury site to deliver and bind bone growth factors and stimulate bone formation at much lower doses than previously reported. However, though promising, our approach of injecting large volumes of gel with protein mixed uniformly through is rather crude when compared with the precise concentration gradients that regulate bone formation in the body.

Over the course of this exploration we have, however, discovered a new unexpected property of nanoclay gels that could potentially make them even more effective at stimulating regeneration. As well as being able to hold onto mixed-in growth factors, we have now found a simple way to precisely pattern the arrangement of these biomolecules within the gel itself. This is very exciting as it could allow us to begin to mimic the intricate patterning so important in natural stem cell behaviour.

The current funding will allow us to explore this property and test ways to apply clay biomolecule patterning in regenerative medicine. It is exciting because we do not currently understand how and why these patterns form and so we are working with physicists specialising in nanoparticle gels to gain new insights into this surprising behaviour. It is also exciting because it allows a new approach to exploring the role of biomolecule patterning in stem cell repair and regeneration. We hope that this work will allow us to harness, more effectively and reliably, the great potential of stem cells to cure disease.

By 2038, 24% 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 UK economy £2bn, 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 bone 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 bed stay, and UK industry by feeding the private biomedical technology sector (as seen through the founding of Renovos Biologics Ltd.)

In the long-term, the implications of this proposal have still broader regenerative applications extending the list of potential beneficiaries to include burn victims, sufferers of diabetes, as well as transplant patients - all with associated broader socio-economic benefits. For example, in collaboration with Dr Nick Evans we have demonstrated the potential of nanoclay gels in treating chronic wounds such as diabetic foot ulcers.

As an example of an application promising near-term socio-economic benefit, Prof. Richard Oreffo and I are developing, through Renovos, the application of nanoclay gel delivery of BMP2 for spinal fusion. The BMP2 product currently licensed for clinical use in this context (called InductOS in UK/EU, INFUSE in the US) employs supraphysiological doses to deliver clinical efficacy and can result in sporadic release, hyper-stimulation of surrounding bone, and soft tissue swelling, which has led to adverse effects. By applying nanoclay gels to localise and sustain the efficacy of greatly reduced doses of BMP2 we have the potential to greatly improve safety profiles. Through this approach we seek to re-build the value-chain for BMP2-based products currently impacted by the adverse clinical effects. The current proposal promises further enhancment of this approach justifying the choice of BMP2 delivery as the initial target. A patent application for the proof of concept is currently being drafted (Barker Brettell PLC) and I plan to formally engage, under NDA, potential partners following successful early stage functional demonstrations (from month 21 onwards).

As well as direct socioeconomic impact, the proposal will benefit emerging research talent within the University of Southampton by immersing graduate students and a postdoctoral researcher (PDRA) in a rigorous multidisciplinary research program, dynamic public engagement and expanding commercialisation activity.

Educational benefit will continue to be pursued through the development of a cutting edge public engagement programme further extending the impact of the stem cell mountain exhibit. 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 have requested funding to enable me to develop, in the first year, a new interactive teaching aid in collaboration with Winchester Science Centre. 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.