Tailoring the atomic structure of advanced sol-gel materials for regenerative medicine through high-performance computing

Increasing life expectancy is resulting in a growing number of surgical procedures to repair weakened or damaged tissues, such as bone and cartilage, with an increasing use of synthetic biomaterials. Current biomaterials used to replace living tissues are unable to cope with ongoing changes in the physiological environment, which is at odds with the tissues, that can self-repair while dynamically adapting to the local conditions. Next-generation biomaterials must be able to trigger the natural self-repair mechanisms of the body, providing a framework which stimulates cells to regenerate new tissues.
Many therapies require the delivery of drugs, but the polymer capsules that deliver them degrade rapidly, releasing all the drug in one go, not necessarily in the right place. The sol-gel process, which assembles silica networks through a chemistry approach, allows one to make biodegradable silica nanoparticles that can deliver drugs or active ions where they are needed.

Materials for tissue regeneration will ideally combine efficient biointegration, controllable biodegradability and cell-stimulation capabilities. Despite their proven ability to trigger the activity of cells that create new tissues, the potential of conventional melt-derived bioglasses (BGs) as next-generation biomaterials is limited by incomplete biodegradation and the difficulty to incorporate them in scaffold templates for tissue-engineering. BGs obtained through a sol-gel route show superior properties, such as higher and controlled solubility; the mild temperature of the sol-gel process allows scaffolds for tissue-engineering to be made, and also allows the incorporation of polymers to make hybrid materials with higher toughness and tighter control of biodegradability than bioceramics. Hybrids are potentially able to share the load with host tissue and respond to biomechanical stimuli.

If any of this potential is to be fulfilled, it is critical to understand the evolution of the nanostructure during synthesis and how to incorporate cations, such as calcium, which affect the material's degradation rate and functionality.

This project will apply breakthrough computer simulations to show how adjustable variables in the sol-gel process, e.g. chemical nature of the precursors (particularly the calcium source), solution pH and stabilisation temperature, affect the nanostructure of the particles, and thus their performance. Such simulations have not been possible previously. The knowledge gained will enable better control over the material behaviour, for instance enabling tailoring the degradation rate of a scaffold to the growth of the target tissue to be regenerated, and would represent a solid foundation to support the rational development of tissue-regeneration biomaterials incorporating sol-gel BGs as a core component.

If substantial advances are to be sought in Biomaterials research, a more fundamental approach to understand the effects which steer the material's behaviour is now required, beyond established but expensive and intrinsically limited trial-and-error approaches. The huge rise in available computer power and methods now enables us to tackle challenges which were out of reach only a few years ago, such as directly modelling the dynamical changes in the sol-gel synthesis, like multiple polymerisation and condensation reactions between modified silica nanoparticles in solution.

We thus now have the unique opportunity to gain fundamental insight which will be a key reference not only for the biomaterials community but also for chemists, engineers and materials scientists who use soft chemistry processing routes. The results from this project will support biomedical and biomaterial research towards better materials for regenerative medicine. These advances will lead in the future to more effective longer-term treatments of musculoskeletal traumas and diseases, especially in older people, with large social and economical benefits.

The results of the proposed research will primarily support the future development of biomaterials with superior long-term repair of aged or damaged tissues, which will improve the treatment of the growing number of patients affected by musculoskeletal conditions in the increasingly ageing modern society. In addition, the development of sol-gel routes for the low-temperature processing of other inorganic glasses in particular and advanced materials generally will be supported.

Immediate impact beyond academia will be in Orthopaedics, with longer term impact in Cancer treatment and Advanced Functional Thin Films (e.g. smart windows). Medical device companies will immediately be able to design and manufacture advanced nanostructured functional materials with the knowledge of how the processing variables will affect the material properties.

Orthopaedic surgeons, patients and health services (e.g. the NHS) will benefit as end users of sol-gel biomaterials in a 20 year timeframe. Patients and UK economy will benefit as patients recover more rapidly, allowing them to return to work. Bone is second only to blood as the most transplanted tissue and current best practice is to transplant bone from the pelvis (autograft). Problems are limited supply of bone and donor site morbidity. Post operative pain is intense, recovery time is long (up to 6 months) and 1 in 4 patients have complications that require further treatment, many needing revision operations. Synthetic grafts are needed that regenerate bone defects to healthy natural bone, reducing reliance on transplants. Frost & Sullivan's analysis of the United States Bone Grafts and Bone Graft Substitutes Market found that the US market earned revenue of $1.60 billion in 2012. The UK's ageing population will benefit from improved quality of life, reducing the burden on a heavily overloaded social care system.

Cancer treatment currently relies on chemotherapy and radiotherapy which cause collateral damage to healthy tissues. Targeted nanoparticles treatments based on sol-gel nanoparticles are being developed, and their technology transfer will rely on companies being able to provide evidence that they understand how they perform.

Our most important outreach targets are clinicians. Interaction with leading clinicians from the Imperial College Medical School (St Mary's for Orthopaedics and Charing Cross for Cancer) will ensure that the materials are designed to meet the end user's needs. Wider dissemination to clinicians will be through a Showcase for Clinicians event and an international network on ageing, led by Prof. Maria Vallet-Regi (Madrid), which aims to bring together clinicians and academics to produce road maps for advancing orthopaedic surgery for the ageing population.

Impact will be widened through international networks. For example, Jones is Chair of Technical Committee 4 (TC04) of the International Commission on Glass (ICG), which has the remit of promoting biomedical applications of glasses and their variants (e.g. hybrids), and has members from ten countries, including industrial members (e.g. GSK, Mo-Sci, Schott, Eli-Lilly). He is also co-Chair of the American Ceramic Society Technical Interest Group on Bioceramics which has a primary aim of increasing links between industry and academia in the area.

Jones' work has consistently attracted interest from the popular press (e.g. Daily Express, Daily Mail). The Victoria and Albert Museum have included a scaffold in their new permanent exhibition of ceramics.

The dynamic research environment will produce the next generation of research leaders; the networking and dissemination activities sponsored by the TYC, to which UCL PI and PDRA are associated, will facilitate engagement with industry and other stakeholders.