A high throughput 3D bone culture system for diagnostic and pharmaceutical screening of new drugs for osteoarthritis

This project builds on our expertise in 3D bone models to develop a high throughput screen where effects of physiological loading and genotype can be assessed.

Arthritis Research UK and Cardiff University have committed a further £5M for the Arthritis Research UK Biomechanics and Bioengineering Centre (http://www.cardiff.ac.uk/arthritis-biomechanics-bioengineering-centre). We are applying our cutting-edge expertise in engineering, bioscience, rehabilitation and imaging to arthritis research in this Centre. The centre involves close collaboration between biomedical scientists, engineers, orthopaedic surgeons, rheumatologists and physiotherapists to translate research for patient benefit. The team investigates normal joint biomechanics and determines how this is influenced by pathology to inform clinical intervention and rehabilitation in musculoskeletal disorders. Discipline hopping opportunities exist to work across disciplines such as Biomedical Sciences, Engineering, Physiotherapy and Orthopaedics.

Outline

This project builds on our expertise in 3D bone models to develop a high throughput screen where effects of physiological loading and genotype can be assessed. Osteocytes are embedded in 3D type I collagen matrix, overlaid with bone forming osteoblasts, which are loaded in a deformable plate using our loading rig (Vazquez et al. 2014). The model will apply physiological loading to human cells. The feasibility of incorporating genetic mutations and simple readouts will be tested. This will reveal new disease mechanisms associated with osteoarthritis and provide a tool to screen new drugs for these diseases.

Healthy ageing is a major health and economical challenge. Osteoarthritis causes pain and disability with substantial healthcare costs. Osteoarthritis is an age-related, ‘silent’ conditions, in which symptoms are not evident until joint damage has already occurred, when treatments cannot reverse the disease. Structural changes in bone drive OA pathology. Mechanical forces exerted on bone during physical activity increase bone mass, and drive adaptation of bone structure. Signals resulting from mechanical loading are primarily generated from the osteocytes, within the mineralised bone matrix, which sense mechanical stimuli and translate them to the bone surfaces where they regulate bone formation by osteoblasts and bone resorption by osteoclasts.

We will identify interactions between genotype and mechanical loading in OA to identify potential disease mechanisms, diagnostics and therapeutics for this disease.

We will:

•adapt our high throughput 3D co-cultures models of bone to incorporate human cells
•mimic the loads which bone cells experience in humans in vivo
•develop methodology to introduce genetic modifications into the cells,
•develop assays to detect anabolic and catabolic responses.

Responses to loading/genetic modifications will be assessed using established molecular and protein assays. Various molecular transfection approaches will be tested.

Interdisciplinary aspects

This is a highly interdisciplinary project between Engineering (loading/strain validation and plate construction) and Biosciences and Medicine (bone cell biology, molecular signaling, genetic modification and pharmaceutical screening)

The successful applicant will join an international team of researchers in a Centre of Excellence for Arthritis Research (http://www.cardiff.ac.uk/arthritis-biomechanics-bioengineering-centre ) and have access to state-of–the art technology to address research questions and long-standing expertise in research translation.

For further information, please contact Dr Deborah Mason.