Relationship Of The Anabolic And Catabolic Responses In Healing A Critical Sized Defect In Rats
Funder
National Health and Medical Research Council
Funding Amount
$329,750.00
Summary
Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bon ....Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bone resorbing response, the catabolic response, may be too high and prevent healing from occurring. In normal bone healing, there is a balance between the anabolic and catabolic response. In disordered bone healing, these responses are out of balance. Several reasonably new treatments are available which can increase the anabolic response or decrease the catabolic response. We have preliminary results showing that with these agents we can bring these elements into better control, and thus drive bone healing. We have optimised an animal model where both the anabolic and catabolic responses can be controlled. In this project, we explore the optimisation of the timing and magnitude of anabolic and catabolic responses in bone healing.Read moreRead less
Multi-centre Randomised Trial Of Early Decompressive Craniectomy In Patients With Severe Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Despite optimal neurosurgical and intensive care therapy, many trauma patients with severe brain injury (typically young males) have very poor long term neurological outcomes. Current knowledge suggests that a key contributor to secondary brain damage which occurs after injury and to poor neurological outcomes is brain swelling and subsequent increase in brain pressure. Present intensive care therapies to control brain pressure are often not effective, and favourable neurological outcomes occur ....Despite optimal neurosurgical and intensive care therapy, many trauma patients with severe brain injury (typically young males) have very poor long term neurological outcomes. Current knowledge suggests that a key contributor to secondary brain damage which occurs after injury and to poor neurological outcomes is brain swelling and subsequent increase in brain pressure. Present intensive care therapies to control brain pressure are often not effective, and favourable neurological outcomes occur in only 20-30% of these patients. Small studies suggest that a surgical operation called decompressive craniectomy (DC) may decrease brain pressure and improve neurological outcomes in these patients. DC involves temporarily surgically removing a piece of skull bone (during the swelling period) and replacing it when the swelling has subsided. DC is done under general anaesthetic in unconscious patients and is used occasionally at present, although due to insufficient research the benefits are controversial. The proposed study is a multi-centre randomised controlled study of best current therapies plus early decompressive craniectomy vs best current therapies alone in selected unconscious patients with severe head injury. The study outcome is patient neurological function measured 6 months after the injury. A study of this type is required before early DC could become a routine therapy in Australia. Next of kin will sign informed consent for the study and then also for the surgery if patients are randomised to surgery. The study will be managed at the Alfred Hospital-Monash University in Melbourne and includes fifteen collaborating ANZ neurotrauma centres over 3.0 years. There are >200 patients in Australia annually in this category with potential for DC to increase favourable outcomes in >40 patients annually. Lifetime costs for these patients with severe disability are > $2.4 million, so there may be substantial economic and social impact.Read moreRead less
Repairing The Injured Spinal Cord: Potential For Human Olfactory Ensheathing Cells
Funder
National Health and Medical Research Council
Funding Amount
$255,990.00
Summary
Spinal cord injury is a major cause of morbidity, particularly among young people involved in road accidents and sports injuries. Finding ways to treat paraplegia is a major goal of neuroscience research. Recently, there has been considerable interest in a special cell found in the olfactory system, the ensheathing cell, which has been found to support regeneration in the spinal cord. Our laboratory has shown that injection of these ensheathing cells into the completely cut spinal cord of adult ....Spinal cord injury is a major cause of morbidity, particularly among young people involved in road accidents and sports injuries. Finding ways to treat paraplegia is a major goal of neuroscience research. Recently, there has been considerable interest in a special cell found in the olfactory system, the ensheathing cell, which has been found to support regeneration in the spinal cord. Our laboratory has shown that injection of these ensheathing cells into the completely cut spinal cord of adult rats can lead to limited functional recovery of hindlimb movement. We used peripheral ensheathing cells because, in humans, such cells can be obtained relatively easily and they reduce problems of tissue rejection. We found that peripheral cells are as effective as previous reports using central ensheathing cells. Our overall aim now is to advance towards the use of olfactory cells in human spinal cord injury, by trialing 3 procedures of clinical relevance: a) to test whether human olfactory cells can also support functional recovery in rats. Human cells can be obtained from the nose by a simple biopsy procedure. If they able to support regeneration, this will open the way for their use in autografts in human paraplegia. b) to delay the time when the olfactory cells are applied to the injured cord. At present, neurosurgeons are not be willing to treat the cord immediately after the injury, because of the risk of causing further damage. This trial is designed to test whether delayed treatment is still effective. c) to test the effectiveness of the cells after bruising, rather than cutting, the cord. Bruising is a more common type of injury in people, hence it is necessary to know how these cells respond to this type of damage. These procedures have been chosen to move our basic research closer to clinical application. Although treatment in humans is still a long way off, these basic studies are essential if conditions like paraplegia are eventually to become treatable.Read moreRead less
Improving Muscle Function After Injury: Novel Tissue Engineering Strategies For Exercise, Surgery And Sports Medicine
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Muscles can be injured by excessive strains when playing sports, in road and workplace accidents, and during plastic and reconstructive surgery. Some surgeries require an unavoidable interruption to the muscle's normal blood supply (called 'ischaemia'). Subsequent return of the muscle's blood supply (reperfusion) is problematic in that a severe secondary muscle injury can ensue mediated by the influx of damaging free radicals when blood flow is restored. Tissue-engineering provides a novel thera ....Muscles can be injured by excessive strains when playing sports, in road and workplace accidents, and during plastic and reconstructive surgery. Some surgeries require an unavoidable interruption to the muscle's normal blood supply (called 'ischaemia'). Subsequent return of the muscle's blood supply (reperfusion) is problematic in that a severe secondary muscle injury can ensue mediated by the influx of damaging free radicals when blood flow is restored. Tissue-engineering provides a novel therapeutic approach to restore muscle structure and function to damaged muscles after injury or disease. Our recent research using controlled release of growth factors from biodegradable hydrogels has exciting application for muscle repairafter injury. We will utilize these cutting edge tissue engineering strategies to deliver to damaged muscles a hydrogel containing controlled delivery (slow release) microcapsules loaded with an anabolic agent (the beta-agonist, formoterol) and-or a growth factor (IL-15) designed to enhance functional muscle repair after three distinct but clinically relevant models of muscle injury: a) crush injury: A model for muscle injuries on the sports field, in the workplace, and those associated with road trauma; b) ischaemia-reperfusion injury: a model for muscle damage associated with surgical interventions, muscle transfers for functional restoration, and other injuries associated with plastic and reconstructive surgery; and c) contraction-induced injury: a model for strain injuries such as hamstring muscle tears that can occur on the sports field. After injury we will assess functional muscle repair using a comprehensive series of histological, biochemical, molecular, immunochistochemical, and physiological techniques. The research has broad application to exercise and clinical medicine; including sports, emergency and rehabilitation medicine, and plastic, reconstructive, and orthopaedic surgery.Read moreRead less
D-Cycloserine And Conditioning: Increasing The Effectiveness Of Exposure Therapy For Fear And Anxiety
Funder
National Health and Medical Research Council
Funding Amount
$400,750.00
Summary
The psychological, social, and financial costs of anxiety problems are among the highest burden-of-disease costs to the community. The most effective long-term psychological treatment for anxiety disorders is cognitive behaviour therapy (CBT), in particular exposure therapy. However only a small minority of individuals receive comprehensive treatment, and a portion of these individuals re-experience symptoms in the long-term. These difficulties are partially due to the cost of treatment and diff ....The psychological, social, and financial costs of anxiety problems are among the highest burden-of-disease costs to the community. The most effective long-term psychological treatment for anxiety disorders is cognitive behaviour therapy (CBT), in particular exposure therapy. However only a small minority of individuals receive comprehensive treatment, and a portion of these individuals re-experience symptoms in the long-term. These difficulties are partially due to the cost of treatment and difficulties with relapse. Recent research has shown that D-Cycloserine (DCS) facilitates extinction in animals and possibly in humans. DCS has the potential to offer a simple, brief, and cost-effective intervention that enhances treatment effects. In the United States the new NIMH director has set research into DCS and exposure to fear as a high priority that is likely to have a significant public health impact. This proposal provides an opportunity for Australian researchers to become involved in a rapidly expanding research field. The research team at UNSW have already established an international reputation in DCS applications, fear conditioning in humans, and clinical trials in humans. They are in a unique position internationally to investigate the means by which DCS exerts its effects and to conduct randomised clinical trials of DCS in recovery from fear in humans.The goal is to test DCS in facilitating exposure and extinction of fear. The research will directly lead to recommendations for clinical application and demonstrate whether the drug has the capability of significantly increasing the success of exposure therapy by reducing the time required for treatment, the rate of relapse, the financial cost of treatment, and the overall burden of anxiety to the community. The fear-conditioning studies will also inform our theoretical understanding of emotion processing and fear conditioning in humans, which in turn will allow clinical applications to be optimised.Read moreRead less
Cellular And Molecular Mechanisms Of Neuronal Repair By Olfactory Ensheathing Cells
Funder
National Health and Medical Research Council
Funding Amount
$218,250.00
Summary
Traumatic injury to the human brain and spinal cord often results in permanent disability. A major reason is that nerve fibres which act as cables connecting different parts of the nervous system are injured and fail to regrow. Failure of adequate repair is due to the fact that the central nervous system is a hostile environment, lacking in growth promoting stimuli and instead possessing growth inhibitory properties. One of the experimental methods used to alter this environment is the transplan ....Traumatic injury to the human brain and spinal cord often results in permanent disability. A major reason is that nerve fibres which act as cables connecting different parts of the nervous system are injured and fail to regrow. Failure of adequate repair is due to the fact that the central nervous system is a hostile environment, lacking in growth promoting stimuli and instead possessing growth inhibitory properties. One of the experimental methods used to alter this environment is the transplantation of olfactory ensheathing cells into the injury site. Ensheathing cells normally support the nerve fibres involved in the sense of smell. Tissue culture studies show that these cells produce on their surface specific types of molecules as well as soluble growth factors that could interact with nerve fibres to promote growth. Although experiments in which ensheathing cells have been injected into rat spinal cords, have resulted in varying degrees of recovery, the question of how they are able to do this remains unknown. The study proposed here will use tissue culture and in vivo models to investigate how ensheathing cells interact with their surrounding cells. In particular we will examine how soluble factors and direct membrane contact contribute to the regeneration of nerve fibres. We will also examine the effects that ensheathing cells have on non-neuronal cells such as astrocytes and oligodendrocytes and vice-versa. A significant outcome of this project is new insight into the complex cellular interaction that occurs to bring about repair in the central nervous system. The findings will pave the way for the future development of olfactory ensheathing cells as an effective therapeutic agent of nerve repair. This could also include genetic manipulation of ensheathing cells such that their properties are optimised specifically to promote regrowth of nerve fibres.Read moreRead less