Master of Engineering Science
Hess, David A.
Flynn, Lauren E.
Cellular therapies targeted at stimulating therapeutic angiogenesis in individuals with critical limb ischemia (CLI) have been under intense investigation. Hematopoietic progenitor cells (HPC) derived from umbilical cord blood have been previously shown to support limb revascularization in animal models of CLI, despite limited cell survival at the site of ischemia. This study attempted to improve HPC survival after transplantation and prolong pro-angiogenic function using human decellularized adipose tissue (hDAT) as a novel cell delivery platform. Compared to HPC conventionally grown on tissue-cultured plastic, hDAT scaffolds were shown to promote viability and proliferation of seeded HPC, and had cell- instructive effects on HPC differentiation through increased expression of cell surface markers enriched on the monocyte/macrophage lineage. For in vivo transplantation studies in a surgically-induced model of CLI, hDAT-seeded scaffolds promoted an accelerated and sustained recovery in limb perfusion, improved functional limb use and increased CD31+ capillary density compared to unseeded hDAT controls.
Summary for Lay Audience
Peripheral artery disease (PAD) caused by the accumulation of atherosclerotic plaque in the distal extremities places an immense burden on national healthcare organizations. Individuals with large end-stage occlusions typically present with symptoms such as gangrene, pain at rest and non-healing ulcers and are commonly diagnosed with the most severe form of PAD known as critical limb ischemia (CLI). Due to a lack of effective treatment options, many patients require lower limb amputation to relieve symptoms and prevent mortality. Fortunately, cellular therapies aimed at stimulating new blood vessel growth and reducing amputation rates have been under intense investigation as an alternative treatment for CLI. Umbilical cord blood (UCB) has been found to contain a rare population of hematopoietic progenitor cells (HPC) that have demonstrated robust regenerative abilities when utilized in animal models of CLI. However, due to the harsh environment that the cells were being introduced into, cell survival and retention at the site of injection remained low. This project aimed to improve HPC survival and retention using a novel cell delivery bioscaffold derived from human adipose tissue commonly discarded as surgical waste. The adipose-derived bioscaffolds were shown to increase HPC survival and proliferation in vitro, and were shown to induce HPC differentiation towards mature cell populations involved in tissue repair. When translated into a relevant animal model of CLI, HPC delivered within the adipose tissue-derived bioscaffold facilitated increased limb blood flow and improved functional metrics of limb use. Overall, these studies aimed to provide pre-clinical proof of concept for improved cell therapies harnessing cell supportive biomaterials for CLI.
Leclerc, Christopher, "Formation of a Vascular Regenerative Microenvironment Within Implantable Human Decellularized Adipose Tissue Bioscaffolds" (2019). Electronic Thesis and Dissertation Repository. 6546.
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Available for download on Friday, September 25, 2020