Bioengineering Synthetic Elastin Conduits For Arterial Revascularisation
Funder
National Health and Medical Research Council
Funding Amount
$624,776.00
Summary
An arterial substitute with both physical and biological properties that mimic those of the human vasculature has long been the holy grail of vascular tissue engineering. We propose synthetic elastin can form the basis of a durable, clinically effective small diameter vascular graft and fill a significant unmet need for a biocompatible vascular substitute.
Biocompatible Synthetic Conduits To Treat Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$421,818.00
Summary
Clinically available synthetic conduits used in vascular repair and bypass are fundamentally incompatible with the vasculature. They cause inflammation at the site of implantation and increase the risk of blood clots forming. We have developed a unique method of binding bioactive protein layers to the surface of all polymeric materials and have shown a significant improvement in their compatibility. Grafts coated using our technology stand to dramatically improve the treatment of vascular diseas ....Clinically available synthetic conduits used in vascular repair and bypass are fundamentally incompatible with the vasculature. They cause inflammation at the site of implantation and increase the risk of blood clots forming. We have developed a unique method of binding bioactive protein layers to the surface of all polymeric materials and have shown a significant improvement in their compatibility. Grafts coated using our technology stand to dramatically improve the treatment of vascular disease.Read moreRead less
Atherosclerosis (hardening of the arteries) is the principal cause of heart attack, stroke and blockage of blood flow to the lower limbs. However, to date none of the biological or synthetic grafts used to bypass the narrowed regions of arteries is ideal. We have shown that lengths of silicone tubing placed into the peritoneal cavity of rats or rabbits becomes covered within 2 weeks by a capsule of granulation tissue (smooth-muscle-like cells and collagen) and mesothelial (endothelial-like) cell ....Atherosclerosis (hardening of the arteries) is the principal cause of heart attack, stroke and blockage of blood flow to the lower limbs. However, to date none of the biological or synthetic grafts used to bypass the narrowed regions of arteries is ideal. We have shown that lengths of silicone tubing placed into the peritoneal cavity of rats or rabbits becomes covered within 2 weeks by a capsule of granulation tissue (smooth-muscle-like cells and collagen) and mesothelial (endothelial-like) cells. The silicone tubing can be removed and the tissue turned inside out such that the endothelial-like cells now line the inside of the tube of living tissue, which resembles a blood vessel. These artificial blood vessels will be grown in the peritoneal cavity of rabbits, then grafted into the right carotid artery to replace a length of removed vessel. Their long-term (3,6,9 and 12 months) patency, reactivity, tensile strength and resistance to clot development will be assessed. Their susceptibility to atherosclerotic plaque development and blockage (as compared with natural carotid artery) will be examined in rabbits fed a cholesterol-enriched diet. Changes in gene expression as the artificial artery progressively develops will be examined, as will the potential to genetically manipulate the artificial artery to improve its functioning. Finally, attempts will be made to grow the vessels entirely in vitro. This novel vascular graft may open new options in the field of arterial reconstructive surgery for replacing or bypassing diseased vessels or as an access vessel for haemodialysis patients with end stage renal failure. This study will also provide new information on the biology of cells found in the peritoneal cavity and their alternative pathways for differentiation.Read moreRead less
I am a pulmonary physician-gene therapist persuing new therapies for pulmonary vascular disease, lung cancer and mesothelioma, COPD and lung transplant rejection
Optimising Islet Transplantation With Vascularized Tissue Engineering Chambers
Funder
National Health and Medical Research Council
Funding Amount
$451,651.00
Summary
Diabetics have high blood sugar levels because cells in the pancreas known as islets produce too little of the hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels. Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of foreign islets, several major problems remain: (1) there are insufficient pancreata (and therefore islets) for transplantation; and (2) the efficiency of delive ....Diabetics have high blood sugar levels because cells in the pancreas known as islets produce too little of the hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels. Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of foreign islets, several major problems remain: (1) there are insufficient pancreata (and therefore islets) for transplantation; and (2) the efficiency of delivery of surviving islet transplants is too low. In pilot studies we have grown a new living pancreatic organ in mice by inserting islets from genetically-related mice together with a structural protein matrix, growth factors and blood vessels inside a plastic chamber. The blood vessels maintain nutrition to the islet cells and simultaneously allow insulin to be released into the bloodstream, thus normalising the high blood sugar in diabetics. In Aim 1 of these experiments we will find the optimal way to grow mature islets in blood vessel-containing chambers in diabetic mice, focusing on (a) the best time to add islets to the chamber - 0, 1 or 2 weeks after establishment, (b) the minimum number of islets to effectively normalise blood sugar and (c) how long we can keep islets alive and functional in chambers, examining periods up to 12 months. In Aim 2 we will test the ability of islet stem cells (provided by our co-investigators at Walter and Eliza Hall Institute, Melbourne) to survive in the chambers and to produce sufficient insulin to effectively lower blood sugar levels to normal in diabetic mice. In Aim 3 we will grow human islets in chambers in special diabetic mice that do not reject foreign tissue, in order to confirm similar behaviour of human islets in this controlled environment. Using this data, we hope to create a research model of functioning islets, that is accessible, retrievable and manipulable, for the further study of diabetes and transplantation.Read moreRead less
Origin Of Cells In The 'artificial' Artery Grown In The Peritoneal Cavity
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Implantation of a foreign object (such as a sterile, flexible plastic tube) into the abdominal cavity of animals induces cells floating in the peritoneal fluid to form a capsule around the object. Over the next 2-3 weeks, the cells differentiate into fibroblasts then myofibroblasts. When this capsule of living tissue (in the appropriate moulded shape) is subsequently grafted into smooth muscle-rich organs such as artery, bladder, uterus or vas deferens to replace excised segments, it gains the s ....Implantation of a foreign object (such as a sterile, flexible plastic tube) into the abdominal cavity of animals induces cells floating in the peritoneal fluid to form a capsule around the object. Over the next 2-3 weeks, the cells differentiate into fibroblasts then myofibroblasts. When this capsule of living tissue (in the appropriate moulded shape) is subsequently grafted into smooth muscle-rich organs such as artery, bladder, uterus or vas deferens to replace excised segments, it gains the structure of the surrounding tissue and the myofibroblasts differentiate further into functional smooth muscle. This raises the question: what is the origin of the cells of the capsule? Our previous studies suggested that monocyte-macrophages stimulated to enter the abdominal cavity in response to the sterile foreign body might be the source of the cells. In the current study we will use transgenic (c-fms EGFP and c-fms Cre Z-AP) mice in which cells of monocyte-macrophage lineage are genetically labelled. These cells can be clearly distinguished from all other cells of the body, and analysis of capsules formed around foreign bodies will give us a definitive answer. We will using micro-array analysis, determine which growth factors-cytokines are important in regulating differentiation of the cells, and the role of physical factors (eg pulsatile stretching). Finally, we will determine whether these cells stimulated to enter the abdominal cavity are capable of differentiating along alternative pathways, such as cardiac muscle or liver cells. Knowledge gained will further the use of the abdominal cavity as a bioreactor in which to engineer tissues for organ replacement therapies. Identification of the mechanisms regulating the (trans)differentiation and biology of the cells may also assist in wound repair strategies to prevent pathologies caused by excessive myofibroblast accumulation and fibrosis.Read moreRead less
Antibody-mediated Dendritic Cell Depletion To Attenuate GVHD
Funder
National Health and Medical Research Council
Funding Amount
$434,510.00
Summary
Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Dise ....Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Disease [GVHD]), despite immunosuppression. GVHD produces serious damage to the internal organs and lining of the mouth and gut. Recovery can also be circumvented by leukemic relapse. GVHD is associated with an increased risk of death and dying after transplantation. To date therapy for GVHD has relied on eliminating the T cells that cause the disease. However for T cells to cause damage they must first be primed with antigen presented on activated dendritic cells. The intensive conditioning therapy required to eradicate the underlying disease before transplantation also activates dendritic cells. Our project seeks to investigate the effects of lethal and non-lethal conditioning on dendritic cells with the aim of validating the use of antibodies designed to deplete activated dendritic cells as therapy for graft versus host disease.Read moreRead less