Research

• Introduction
• Hard tissue replacement and biology
• Orthopaedic Cell and Tissue Engineering
• Biomaterials in dentistry and for drug delivery
• Forming and processing technology
• Interfaces and sensors

Introduction

Whilst research fields have not been formally grouped into major topics, specific activities, variously relating to bone and joint replacement, orthopaedic/musculoskeletal systems, dental applications and tissue engineering are well represented.

We are also entering a new phase of more fluid inter-relationships within the IRC, which will evolve, incorporating growth areas of cardiovascular materials, biosensors and biomaterials manufacture.

Valuable new collaborations have been established with the School of Medicine and Dentistry, notably links with Surgery, Cell and Molecular Biology and Gastroentrology. The inclusion of the IRC within the Centre for Materials Research (CMR) will facilitate links with Physics and Materials.

Research includes the following themes.

Hard tissue replacement and biology

Work on bioactive ceramics has been extended with further attention to biomechanics and mechanisms to failure. On the macroscale, failure has been shown to propagate out from regions of initial damage; at the trabecular scale observations of stress concentration and plastic collapse have been made. The hydroxyapatite/high dentistry polyethylene composite system is being investigated for skull bone reconstruction, and both impact resistance and osteoblast cell response has been assessed. Complementary work on bioceramics has continued with evaluation of hydroxyapatite structures and the influence of silicon content on bioactivity. Work on antigen presentation at the bone implant interface continues with further studies on wear particles, and the involvement of macrophages in antigen presentation to T lymphocytes. There is now clear indication of a general signalling molecule upregulation. Wear particle generation for metal on metal arthroplasty has been quantitiated using wear simulation, but as well as conventional wear, a range of stimulated ambulatory activities, including running, slow walking and jogging have been included. These have revealed up to a ten fold increase in volumetric wear. There is indication that a 40 mm hip-bearing diameter reduces early wear volume, though metallurgical structure (Co-Cr-Mo) does not influence wear patterns. Mesenchymal sstem cell studies have allowed establishment of osteogenic lineage, and thereby helped gauge response to different hydroxyapatite microstructures to underpin work on bone graft optimisation.

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Orthopaedic Cell and Tissue Engineering

Cell nucleus displacement at intact tendon fascicles undergoing strain has allowed assessment of local strain fields, and in particular, the effects of changes in collagen and proteoglycan make-up. Mesenchymal stem cells seeded on RGD - functionalised polymers for tissue engineering have been studied, and specific gels found to help maintain cell viability in constructs, facilitating cell differentiation. Studies made of shear strain at chondrocytes in intact cartilage and in agarose 3-D constructs have demonstrated that shear strain varies both with depth and across the external surface. Simultaneous confocal imaging has been achieved using a newly developed test rig. In the work conducted, spontaneous baseline Ca2+ transients were seen to be directly upregulated by, for example, serum exposure with delayed effects associated with compression, suggesting such response to be activated by upstream signalling. Work is ongoing on GFP-visualised cytoskeletal structures, and results suggest a high degree of cell structural and mechanical heterogenetry. Limitations of O2, supply to deeper chondrocytes is a key problem in cartilage tissue engineering, and O2, glucose and lactate monitoring at different depths indicated time dependent changes due to cell respiration. Dynamic compression, both continuous and intermittent, revealed loading dependent proteoglycan synthesis. Exposure of chondrocytes to TGFb3 showed 35SO4 and [3H]-thymidine incorporation to be enhanced by compression, and mediated by integrin 25b1. Evidence was found for reversal of IL-1b effects through IL-4 and dynamic compression. Solute transport through connective tissue has been computationally modelled and passive transport correlated with cyclical loads utilising poroelastic theory.

Work on vascular ageing continues. Elastin has been cycled to arterial pressures (up to 106 cycles), and eventual fatigue fracture characterised. Work with a recently designed compliant ended vascular stent indicates reduced vascular intimal hyperplasia; this study has been underpinned by non-invasive measurement of vascular changes using micro-CT. A novel non-invasive vascular pulsewave velocity measuring system is now in use in several UK and overseas clinical centres. Related work on renal failure patients has helped characterise vascular ageing in such patients.

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Biomaterials in dentistry and for drug delivery

Fluoride bioavailability is important in caries resistance. In work on glass ionomer cements, fluoride and monofluorophosphate release were determined. Alginate impression materials loaded with antiviral agent are under investigation to achieve a self-disinfection capability. Iontophoretic transport of FITC-dextran through mucosal tissue is being investigated in vitro for possible use in transbuccal drug delivery. Plasticised, and compliant, forms of PEM/THFM are being tested for drug release. Silicones for controlled salicylate drug delivery to skin as anitiviral therapy have been investigated. Silicone based materials are vulnerable to microbial biofilms, and Cadida adhesion and cytotoxity has been evaluated at a range of chlorhexidine loaded materials. To improve temporary denture linings, development of a gel formulation comprising butylmethacrylate/ethylmethacrylate copolymer and a citrate plasticiser has been undertaken; the material provides better resistance to hardening (a result of plasticiser loss) with improved handing and gelation properties.

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Forming and processing technology

Polyurethane synthetic work is ongoing, and materials with various mechanical and surface properties have been produced, notably using surface grafted polar groups to attempt to increase biocompatibility. Porous polyurethane has been formed using CO2 supercritical fluid (SCF), with indomethacin incorporated as a model for drug delivery. Porous alginates have been produced with different level of porosity employing dispersed oil phases. SCF has allowed apatite production with incorporated carbonate as a possible phase pure material. Sodium substituted carbonate apatite has been produced using an aqueous-organic emulsion. Various synthetic and processing routes have been developed for the production of TiO2 particles, including surfactant stabilised microemulsions and SCF. Organophosphoric acid has allowed covalent bridging between hydroxyapatite and poly(HEMA) to produce a more stable composite. Laser surface ablation of hydroxyapatite is being used in order to control surface topography.

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Interfaces and sensors

Screen printed carbon electrodes have been used as an electrochemical surface for chlorophyll detection as an environmental biomaker. To facilitate selective detection, PVC membranes variously modified with surfactant and lipid have been tested. Low contamination biosensing has been achieved using parallel laminar microflows using one flow carrying sample, and a second as a renewing fluid barrier layer. Biofouling remains a major obstacle to stable biosensor use, and work with microporous polymeric barriers has confirmed open pore occlusion by proteins is a major cause of electrode drift, with differences observed between albumin, fibrinogen and hyaluronan model systems depending on pore diameters. Use of conductive poly(pyrrole) films with a range of topographies and loaded bioactive components has served as a surface for keratinocyte growth. By impedimetric measurements, cell growth, confluence and differentiation are being monitored. Protein biofilms formed at planar substrates are being investigated by nanoindentation, an alternative for cross comparison of protein structure of surfaces. Chronic lymphatic leukaemia cells are being studied at hydrogel surfaces, variously loaded with bioactive solutes as a model for cell-surface interactions. Porous polycarbonate membranes variously depleted of a hydrophilic surface layer and used as substrate for osteoblasts, has shown cell interaction effects.

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