The Development of a Multi-Modal Pro-Angiogenic Therapeutic for the Treatment of Peripheral Arterial Disease

Atherosclerotic peripheral arterial disease is a common and debilitating condition, which results in reduced blood flow to the lower limb. 15% of patients with peripheral arterial disease go on to develop “end stage” critical limb ischaemia. Current treatment options include bypass surgery or endovascular techniques such as stenting and angioplasty. These treatments carry risks and cannot be used in all patients. Therefore, a not insignificant cohort will go on to need an amputation which creates a huge burden for individuals and health care systems. Therapeutic angiogenesis aims to use pro-angiogenic agents such as genes, proteins, mesenchymal stem cells, and small molecule drugs to bring about angiogenesis or new blood vessel growth in ischaemic tissues.

The following experimental chapters describe the results of a multimodal pro-angiogenic treatment comprising human mesenchymal stem cells and the small molecule drug desferrioxamine in a chitosan gel carrier. Promising results are demonstrated in a murine model of hindlimb ischaemia both in terms of real time improvement in perfusion and in terms of increased cellular markers of new blood vessel formation. The addition of thermosensitive liposomes to deliver pro-angiogenic agents in a temporally and spatially controlled manner adds a further level of sophistication in the second experimental chapter. By combining lysolipid-based thermosensitive liposomes and an injectable chitosan hydrogel matrix, the “Lipogel” compound allows a localised, adjustable and time dependent delivery of multiple therapeutics. This approach represents an exciting delivery platform which could potentially be used to deliver a vast array of therapeutics in any number of disease processes.