We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has not previously been possible to accurately exp ....We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has not previously been possible to accurately explore the relationship between prothesis wear and PO, or the progression of PO, because of a lack of techniques to image and measure the volume of PO around metal prosthesis components. We have developed a means to accurately and reproducibly measure the volume of bone loss, using CT, and will do so longitudinally in joint replacement patients to obtain the first information about the progression of PO. New computer based methods will be used concurrently to relate prosthesis wear and migration parameters to PO. Patients who come to surgery for replacement of failed prostheses will be investigated further by analysis of the tissues involved in the bone loss around prostheses. Basic science experiments will seek to understand the underlying causes of PO and the findings will be important in interpreting the clinical results. An animal model will be used to seek approaches to inhibiting the pathological response to wear particles. The significance of these studies is that they will lead to improved outcomes for joint replacement patients, increasing the interval to revision surgery, which is both extremely costly and brings an attendant morbidity and mortality.Read moreRead less
Mechanisms Of Premature Cranial Fusion: Role Of Retinol Binding Protein 4 In Osteogenesis And Suture Fusion
Funder
National Health and Medical Research Council
Funding Amount
$555,855.00
Summary
Craniosynostosis is a condition where the skull bones fuse prematurely, affecting skull shape, vision and cognition. It occurs in 1 in 2,500 births. The only treatment is surgery, which is life-threatening, costly and may need to be repeated. By studying how fusion happens in this project we may be able to devise therapies to minimize the risks and need for re-operation. Here, we hope to show that modification of a single substance in the skull of mouse models can prevent premature bone fusion.
Tyrosine Kinase Receptor C-ros-oncogene 1 Mediates Twist-1 Haploinsufficiency Induced Craniosynostosis In Children: A Novel Therapeutic Target
Funder
National Health and Medical Research Council
Funding Amount
$562,863.00
Summary
Children with Saethre-Chotzen syndrome exhibit premature fussed coronal sutures, and other skull/ skeletal malformations. Surgical intervention is the only treatment option to ensure optimal cognitive and skeletal development. Our studies have identified a candidate molecular pathway that regulates bone formation by cranial bone cells from these patients. Targeting these key molecular signalling components with chemical inhibitors will help prevent the premature fusion of cranial sutures.
Histone Demethylase KDM6A Is A Novel Target For Treating Craniosynostosis In Children With Saethre-Chotzen Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$548,854.00
Summary
Children with Saethre-Chotzen syndrome exhibit premature fused coronal sutures, and other skull/ skeletal malformations. Surgical intervention is the only treatment option to ensure optimal cognitive and skeletal development. Our studies have identified a candidate molecular pathway that regulates bone formation by cranial bone cells from these patients. Targeting this key molecular regulator with chemical inhibitors will help prevent the premature fusion of cranial sutures.
The Role Of Osteocytes In Particle Induced Osteolysis
Funder
National Health and Medical Research Council
Funding Amount
$457,196.00
Summary
Hip replacements often fail due to the loss of adjacent bone. Metal or polyethylene particles are produced as the prosthesis bearing surface wears but how do these particles lead to bone loss? Our work suggests involvement of osteocytes within the bone mineral, which are increasingly understood to drive bone physiology and pathology. We will explore the role of the osteocytes by examining their response to particles, which may identify a new target to prevent particle-induced bone loss.
New Methodology for the Stereoselective Construction of Oxygen Heterocycles and Rare Sugar Analogues. The overall goal of this research is to develop new synthetic methods, particularly ones that exhibit high levels of stereocontrol. Current research efforts are directed towards the stereoselective construction of oxygen heterocycles and rare sugar analogues both in their racemic and chiral forms utilising 1,2-dioxines containing tethered hydroxyl moieties as the key chemical precursors. It is e ....New Methodology for the Stereoselective Construction of Oxygen Heterocycles and Rare Sugar Analogues. The overall goal of this research is to develop new synthetic methods, particularly ones that exhibit high levels of stereocontrol. Current research efforts are directed towards the stereoselective construction of oxygen heterocycles and rare sugar analogues both in their racemic and chiral forms utilising 1,2-dioxines containing tethered hydroxyl moieties as the key chemical precursors. It is envisaged that these investigations will lead to the development of simple experimental protocols for the synthesis of new bioactive organics.Read moreRead less
The recovery of Cu from chalcopyrite-pyrite containing concentrates, ores and tailings. Chalcopyrite, a major source of Cu, is often associated in ores with the valueless mineral pyrite. The development of more efficient methods for the retrieval of the Cu is of considerable economic importance to Australian minerals processing companies. We aim to develop methodologies allowing the more efficient :
- separation of chalcopyrite and pyrite;
- leaching of Cu from ores and tailing in a heap leach ....The recovery of Cu from chalcopyrite-pyrite containing concentrates, ores and tailings. Chalcopyrite, a major source of Cu, is often associated in ores with the valueless mineral pyrite. The development of more efficient methods for the retrieval of the Cu is of considerable economic importance to Australian minerals processing companies. We aim to develop methodologies allowing the more efficient :
- separation of chalcopyrite and pyrite;
- leaching of Cu from ores and tailing in a heap leach environment and
- leaching of Cu in a concentrated chalcopyrite-pyrite reactor environment.
These aims will be achieved via an integrated surface-solution speciation approach allowing the manipulation of surface properties.
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Development of Dry Coated Pigment Particles: Durability and Dispersion. Tiwest is the only business in the world that mines, separates, refines and manufactures titanium dioxide products in one region. Tiwest has a major impact on the Western Australian economy with more than 700 full time and contract jobs, export earnings of $400M (in 2004) and regular incomes for an estimated 500 businesses. The current wet pigment particle coating process, to ensure ease of handling and longevity, is a major ....Development of Dry Coated Pigment Particles: Durability and Dispersion. Tiwest is the only business in the world that mines, separates, refines and manufactures titanium dioxide products in one region. Tiwest has a major impact on the Western Australian economy with more than 700 full time and contract jobs, export earnings of $400M (in 2004) and regular incomes for an estimated 500 businesses. The current wet pigment particle coating process, to ensure ease of handling and longevity, is a major cost. An optimised pigment dry-coating process would ensure Tiwest's competitiveness through reduced processing costs and improved performance. This development has the potential to increase Tiwest's profitability by 10%.Read moreRead less
Characterising Novel Alternative Splicing Networks That Promote Tumour Cell Plasticity
Funder
National Health and Medical Research Council
Funding Amount
$609,329.00
Summary
During cancer progression, tumour cells can change their properties and become more aggressive and resistant to therapies. We have identified an important regulator of this tumour cell transition, called “Quaking”, which causes widespread changes in gene splicing. We aim to investigate how "Quaking" causes changes in gene splicing and what the effects of these splicing changes are in tumour cells.
Determination Of Irradiation Dose Efficacy For Use In Impaction Grafting At Revision Joint Replacement
Funder
National Health and Medical Research Council
Funding Amount
$411,517.00
Summary
Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more than ten years in some centres. A high incidence ....Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more than ten years in some centres. A high incidence of early complications of this procedure have included loss of fixation within the bone. Fracture of the bone around prostheses has also reported in some centres. These events require more surgery, putting the patient at higher risk greater complications and longer rehabilitations. Recent improvements in surgical technique and donor bone preparation have improved results. A current debate questions whether the dose of irradiation can be reduced from 25 kGy, while maintaining sterility of allografts. The risk of bacterial contamination in allografts is low, and irradiation reduces the mechanical strength of the graft, contributing to complications when irradiated bone is used. The benefits of decontaminating the bone may be outweighed by the higher risk for failure due to poor bone quality and resulting prosthesis instability. We will use ISO standards to test the validity of radiation dose for sterilising bone ex vivo. In the absence of controlled human studies, our aim is also to compare the results of impaction grafting with non-irradiated bone versus bone irradiated at current doses used by Australian bone banks, and lower doses indicated by ex vivo testing. We will use a large animal model of revision hip replacement, with precise measures of prosthesis stability. The results of this study will guide clinical decisions regarding the efficacy of current bone graft preparation procedures and the use of irradiated bone in human hip replacement surgery.Read moreRead less