The Lincoln Centre currently provides support for research into Bone and Joint Diseases and Hand Surgery through the funding of three research directors and the provision of funding for specific research projects and education activities.
Sutton Arthritis Research Laboratories - A/Prof Christopher Jackson
Since 2009, Associate Professor Chris Jackson has received funding for his position as Director of Sutton Arthritis Laboratories within the Kolling Institute on the Royal North Shore campus, University of Sydney. His team’s research focuses on cellular and molecular mechanisms of inflammation. Some specific projects relate to stopping the pain and swelling of patients affected with rheumatoid arthritis, attempting to prevent or limit the bone and cartilage destruction which occurs in the joints of these patients. The laboratories have developed novel molecular biological techniques to manipulate cellular systems; create new bone for patients with bone loss from multiple reasons such as inflammatory arthritis, fractures, infections and the like; modulation of inflammatory cell behaviour to improve disease severity in rheumatoid arthritis.
In 2016 the major project in the Sutton Arthritis Laboratory was in understanding the mechanism of activated protein C (APC) as a biological therapy in rheumatoid arthritis (RA). We have shown that APC can directly target RA features by i) normalising the body’s immune response, ii) preventing blood vessel damage and iii) inhibiting synovial tissue invasion. Thus, unlike other biological treatments currently used for RA, which deplete specific inflammatory molecules or cells, APC has a broader action and is safe. These functions of APC are mainly mediated by its specific receptor endothelial protein C receptor (EPCR). Our most recent results show that APC can prevent arthritis in the collagen-induced arthritis model, a model of human RA. However, it cannot treat the disease once it is established. Similar results were seen in another model of RA, antigen-induced arthritis. Based on our recent research, we now hypothesise that the high levels of tumour necrosis factor (TNF) in the disease block EPCR so that APC can no longer function - and that freeing up EPCR will allow APC to treat active disease. We aim to now conduct these experiments and provide proof-of-concept data for ultimate translation into human clinical trials.
Department of Hand Surgery and Peripheral Nerve Surgery - Dr Richard Lawson
Hand Surgery is the management of afflictions of the hand and wrist, management of upper limb conditions that affect hand function and microsurgical reconstruction of the hand and upper limb. Hand surgery deals with the skin and its contents, all of which are based on the skeleton of the hand and upper limb; the joints which allow positioning and function of the hand; the tendons and their muscles which control joint motion; the nerves which provide the messages for muscle control and activity, supply sensation to the skin and instruct the position and integrity of joint behaviour; and the vessels which provide life for all tissues, bone and soft tissue.
In 2002, Professor Jagdeep Nanchahal transferred from London to Sydney to take up this position within the Department of Hand Surgery and Peripheral Nerve Surgery at Royal North Shore Hospital, while continuing his collaborative relationship with the Kennedy Institute of Rheumatology in London. Professor Nanchahal returned to London in 2005. During his tenure he was instrumental in developing pathways to modulate inflammatory disease, in collaboration with the Kennedy Institute and with the Sutton Laboratories within the Kolling Institute; developed his approach to the acute management of severe lower limb injuries, subsequently adopted by the British Medical Council as the gold standard for the management of these injuries in the UK; and investigated the causes and management at a molecular level of Dupuytren’s contracture.
In 2005, Dr Richard Lawson was appointed to this position. The emphasis of his coordinated research projects is the review of clinical conditions, their management, and how to obtain optimal outcomes, as well as overseeing basic scientific projects directed towards tendon healing, optimal suture techniques within tendons, bone healing and anatomical studies.
The Department of Hand Surgery and Peripheral Nerve Surgery is involved in numerous research projects within Royal North Shore Hospital and North Shore Private Hospital. This research is run in collaboration with pharmaceutical companies, physiotherapists, the Department of Orthopaedics, quadriplegia units, the Maxwell Murray Biomechanics Laboratory and the Sutton Laboratories. In 2016 the department conducted 10 clinical studies, 6 anatomical and biomechanical studies, 3 case studies/series and 3 literature reviews. We hosted 12 fellows and graduated 2 research students and published 9 papers in Hand Surgery journals and 2 book chapters.
Murray Maxwell Biomechanics Laboratory - Dr Elizabeth Clarke
The Lincoln Centre helped to establish the position of Director of Murray Maxwell Biomechanics Laboratory, now located within the Kolling Institute on the Royal North Shore campus, University of Sydney. Dr Richard Appleyard was the inaugural Director, leaving in 2010 to join the Macquarie University Hospital campus.
Dr Elizabeth Clarke was appointed as Director of the Murray Maxwell Biomechanics Laboratory in 2010. She has a background in Mechanical Biomedical Engineering (the University of Sydney) and she completed her PhD in spinal biomechanics in 2008. Dr Clarke's research themes are injury biomechanics, tissue and joint biomechanics, and medical imaging biomechanics. The Murray Maxwell Laboratory collaborates closely with other bone and joint research laboratories and Orthopaedic and Hand surgeons. Since Dr Clarke's appointment her research has developed novel MRI techniques to measure large strain behaviour of soft tissues, novel MRI techniques to track 3D joint and tendon motion, investigations of paediatric spine strength to understand different spinal injury risks and mechanisms in children, and investigations of the effects of injury loading conditions on the severity of spinal cord injury. Dr Clarke's collaborative research has also discovered ways that tendinopathy changes the properties of tendons, ways to improve bone strength after removal of orthopaedic plates, tendon suturing techniques to improve strength, and characterisation of properties of new orthopaedic screw designs.
In 2016 the major projects in the Murray Maxwell Biomechanics Laboratory were in injuries leading to osteoarthritis and tendinopathy. Our major discoveries were that (i) relatively mild joint injuries (not only severe injuries) are a risk for both osteoarthritis and severe joint re-injury; and (ii) different tendon types respond differently to mechanical loading and injury. We have also been working on developing new MRI methods to image the spinal disc and making road-travel safer for older people, motorcycle users and babies. In the past 12 months, our laboratory had 16 journal articles accepted including one in the Journal of Biomechanics, two in the Journal of Orthopaedic Research and one in Osteoarthritis and Cartilage. We attracted $135,000 in research grants and $20,000 in industry contracts, and supervised 5 postgraduate students, 3 Honours students, 1 MD research project and 4 Engineering internships.
PREVIOUS SUCCESSFUL GRANT APPLICATIONS
Successful 2018 Research Applications
Dr Clarke – Kolling Institute/University of Sydney, Biomechanics/Surgery – Kangaroo Tendon Xenograft for Hand Surgery – Awarded $39,408
This project explores the functional suitability of kangaroo tail tendons as a natural, reliable, off-the-shelf graft for tendon surgery in the human hand. Tendons connect muscle to bone to facilitate movement. If tendons are severely injured or diseased, or if joints are unstable or painful, then surgical repair or reconstruction using a graft material may be performed to restore function. We will compare the mechanical and structural properties of kangaroo tail tendons with human cadaveric tendons from the hand, foot and forearm to determine the functional suitability of this novel Australian graft material for hand surgery.
Professor Goldys – University of New South Wales, Science – Progression of Cartilage Degeneration/Repair Awarded $48,571
The joints of the hand are cushioned by soft cartilage. However, cartilage can break down resulting in pain and the loss of function (arthritis). Cartilage is very slow to repair itself and there are no reliable treatments to restore it. We need to know more about how cartilage breaks down and repairs, but all the ways of collecting advanced information also destroy the sample being studied. This means we can’t study how these processes progress overtime. However, we have a new technology called hyperspectral microscopy which collects advanced information on the state of cartilage without damaging it which we plan to use to solve this problem.
Dr Tsang – University of Sydney, Science – Stem Cells for Flexor Tendon Repair – Awarded $33,530
Techniques to effectively repair injured tendons are currently unreliable. Rupture of repaired tissue occurs in approximately 5% of cases during the 10-week period after the initial injury and long -term complications such as adhesion formation, joint contracture and cold sensitivity can occur in up to 66% of patients. Investigation into techniques that can improve the quality and strength of the repair and reduce complications are warranted. This study utilizes an established animal model of flex or tendon injury to determine whether treating injured tendons with stem cells, at different times after injury, can improve the quality and/or speed of healing.
Successful 2017 Research Applications
1. The role of PAR1 and PAR2 in the regulation of anti-infection ability of inflammatory cells and mucosal epithelium where infection may trigger rheumatoid arthritis
Investigators: Meilang Xue, Christopher Jackson
Summary: The cause of rheumatoid arthritis (RA) is not clear however bacterial infection of gut and/or oral cavity is a trigger for RA onset in susceptible individuals. Two proteins named as PAR1 and PAR2 are involved in bacterial detection and arthritis progression. This project will examine the function of PAR1 and PAR2 in the regulation of bacterial killing ability of immune cells and the anti-infection response of oral and gut epithelial cells.
2.Extensor tendon excursion at the proximal phalanx: clinical application to rehabilitation programs
Investigators: Ray Jongs, Sarah Tolerton, Belinda Smith, Mark Hile
Summary: This project investigates a variety of finger exercises on human cadaveric hands to determine which combinations create the most extensor tendon motion, therefore determining which are the most effective exercises for extensor tendon glide
Successful 2016 Research Applications
Three grants were awarded in 2016 to support the following projects:
1. Effect of combined conservative therapies on clinical outcomes in patients with thumb base osteoarthritis: a randomised, controlled trial (COMBO).
- Dr Sarah Ferriera de Meneses
Osteoarthritis (OA) is a chronic, disabling and prevalent disease. Hand OA is the most common subtype, affecting 43% of the population worldwide. Hand function is considerably impaired when the thumb base is affected, including difficulty with opening jars, fastening buttons, writing and pinching. Despite its impact, there are no specific recommendations regarding the best treatment for thumb base OA. This study aims to determine the effect of a combination of therapies, namely, education on self-management and joint protection, splint, hand exercises and topical anti- inflammatory, compared to education on self-management and joint protection alone for people with thumb base OA.
2. The functions of PAR1 and PAR2 during the onset and development of infection-related rheumatoid arthritis in a mouse model.
- Dr Meilang Xue
Arthritis is the major cause of disability and chronic pain in Australia, and rheumatoid arthritis (RA) is one of the most damaging forms, with about 30 % of patients unable to work after 3 years of disease. Proteinase activated receptor (PAR)1 and 2 are the members of G-coupled receptors. Although strongly implicated in joint inflammation and destruction, the exact functions of PAR1 and PAR2 in RA are still unclear. This study will use PAR1 and PAR2 gene knockout (KO) mice and collagen- induced arthritis (CIA), a widely recognised as the ‘gold standard’ experimental model for investigation of RA, to address the role of PAR1 and PAR2 in RA.
3. A quantitative atlas of three-dimensional architecture of human forearm and hand muscles in vivo.
- Dr Bart Bolsterlee
Current understanding of forearm and hand muscle function is largely based on anatomical measurements from human cadaver muscles of elderly people. Through new imaging techniques it is now possible to measure muscle structure in living humans with unprecedented levels of detail. In this project, a quantitative atlas will be made of the three- dimensional architecture of hand and forearm muscles in living humans. The atlas will provide the most detailed description of hand and forearm muscle architecture to date. These data will generate fundamental insights into the function of hand and forearm muscles, and could be used to inform surgical decisions.
The Lincoln Centre has funded the projects of Ferriera de Meneses ($46,662) and Xue ($26,900) and Bosterlee ($22,596).
Successful 2015 Research Applications
Three grants were awarded in 2015 to support the following projects:
1.Effect of Metformin on palmar fascia cells from patients with Dupuytren’s contracture.
- Dr Margaret Smith
Dupuytren's contracture (DC) is a disabling condition where tissue in the palm of the hand thickens and stiffens, causing the adjacent fingers to curl and lose function. The cells (myofibroblasts) causing the contracture have been stopped in other similar diseases (such as in lung and heart fibrosis) by a commonly-prescribed, glucose-lowering drug, metformin. We propose here to test whether metformin can normalise the molecular biology and behaviour in cells from abnormal tissue of DC patients (removed from the palms as part of their already planned surgery (fasciectomy) to release the contracture of their fingers). If metformin proves to beneficially modify the cells that drive DC, this may provide a new therapeutic approach in this disease.
2.What causes thrombotic complications in rheumatoid arthritis?
- Dr Helena Liang
Arthritis is the major cause of disability and chronic pain in Australia. The common clinical symptoms of Rheumatoid Arthritis (RA) include pain, swelling, stiffness and deformity of the hand and foot joints. In addition RA patients are known to be two times more likely to develop cardiovascular disease and venous thrombosis, but the reason for thrombotic complications in these patients remains unclear. This study addresses thrombosis and the role of an endogenous anticoagulant, which has a novel therapeutic potential in RA.
3.Effects of localised compressive loading on tendon health.
- Dr Elizabeth Clarke
Tendons connect muscles to bones, allowing movement of the joints. Damaged or diseased tendons can cause chronic pain, disability and weakening that can lead to rupture. Normal tensile loading is important for maintaining tendon health but some tendons may experience localised compression that could lead to tendon disease. Localised compression of tendons may occur near fracture fixation implants, at sites of inflammation or during abnormal joint motion. This study uses controlled mechanical loading of tendons to determine the effects of localised compression on tendon health. This understanding may provide insight to the mechanisms of some common tendon diseases and could guide therapies to prevent or treat them.
The Lincoln Centre has funded the projects of Smith ($26,982) and Liang ($30,000) and Clarke ($28,087).
Successful 2014 Research Applications
Three grants were awarded in 2014 to support the following projects:
1.Effects of mechanical loads on tendon health and tendon type
- Dr Elizabeth Clarke
Tendons connect muscles to bones, allowing movement of the joints. Damaged tendons (also “tendinopathy” or “tendonitis”) can cause chronic pain, disability and weakening that can lead to rupture, and this is particularly common in the hand. Load bearing tendons (flexors) and positional tendons (extensors) vary in their configuration and loads typically experienced. This study investigates whether different types of tendons respond biologically and mechanically in the same way to a range of loading intensities, using a “cell culture” model for 3 weeks. Differences in response to load for different tendons may affect physical therapy to prevent or treat tendinopathy.
2. CROSSFIRE: Combined Randomised and Observational Study of Surgery for Fractures In the distal Radius in the Elderly
- Prof. Ian Harris
Fractures of the distal radius (also called wrist fractures) are the most common type of fracture seen. Currently, standard treatment involves treating these with surgery using a plate and screws despite high quality evidence that this does not provide a significant benefit over alternative treatments, including non-operative treatment. We aim to perform a high quality study comparing plate fixation to non-operative treatment in a plaster cast. By providing high quality evidence and involving surgeons in Australia, we aim to strengthen the evidence base around this common condition in order to guide future treatment, potentially improving outcomes and saving valuable resources.
3. Can the combination therapy of APC and anti-sPLA2V yield a novel treatment for rheumatoid arthritis? A cellular approach.
- Dr. Meilang Xue
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that typically affects the small joints in hands and feet. In RA, the joint lining layer swells, invades and destroys surrounding tissues, and eventually result in bone erosion and joint deformity. The major cells accounting for RA joint swelling and damage are rheumatoid synoviocytes (RASF) within the joint. Activated protein C (APC) is a natural anti-clotting agent with strong anti-inflammatory properties. We have found that APC can suppress the inflammation and destructive properties of RASF. However, our recent data showed that an enzyme, known as group V secretory phospholipase A2 (sPLA2V), inhibited APC-mediated anti- inflammatory effects in RASF. This project will investigate whether addition of a sPLA2V inhibitor can increase the efficacy of APC in the inhibition of destructive properties of RASF, thus preventing or limiting bone and cartilage destruction within the RA joint in vitro.
The Lincoln Centre has funded the projects of Clarke ($17,881) and Harris ($40,000) and Xue ($36,310).
Successful 2013 Research Applications
Three grants were awarded in July 2013 to support the following projects:
The diabetic hand: understanding the mechanisms of tendinopathy
- M Smith, Raymond Purves Research Laboratories, Kolling Institute, University of Sydney
Tendon disease (tendinopathy) has a greater incidence in hands of diabetic patients than in healthy people. The mechanisms that drive this change are presently unknown, and as a result specific therapies are lacking. We will examine changes in tendon in diabetic and non-diabetic mice, and established tendon culture models, to determine how elevated glucose alters the structure of tendon and the role of the tendon cells in this process. The results from this work will aid in the development of treatments with improved outcomes for this crippling condition.
2. In vivo ultrasound assessment of the effect of flexor synovectomy on median nerve and flexor tendon motion within the carpal tunnel
- AJ Beard, Department of Hand Surgery, Royal North Shore Hospital
This study will investigate the effect of open carpal tunnel release +/- synovectomy on the motion of the median nerve. Patients presenting with carpal tunnel syndrome will undergo pre-operative ultrasound imaging of the median nerve and flexor tendons with the wrist in extension, neutral and flexion. The position of the median nerve and flexor tendons will be recorded in these positions with and without stress (gripping). Patients will then be randomised to undergo an open carpal tunnel release or an open carpal tunnel release with synovectomy. Post-operative ultrasound assessment of median nerve and flexor tendon motion will be performed at 5 weeks and 6 months.
3. Can activated protein C reverse the aggressive properties of rheumatoid synoviocytes?
- M Xue, Sutton Arthritis Research Laboratories, Kolling Institute, University of Sydney
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that typically affects the small joints in hands and feet. In RA, the joint lining swells, invades and destroys surrounding tissues, and eventually result in bone erosion and joint deformity. The major cells accounting for RA joint swelling and damage are rheumatoid synoviocytes (RASF). RASF are not only responsible for joint destruction but also sustain the inflammation in RA. Reversing the damaging phenotype of RASF is a potential option for RA treatment. Activated protein C (APC) has strong anti-inflammatory properties. This project will investigate whether APC can inhibit the aggressive properties of RASF thus preventing or limiting bone and cartilage destruction within the RA joint.
The Lincoln Centre has fully funded the projects of Smith ($39,311) and Beard ($39,551) and partially funded that of Xue ($21,138).