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Temporal Modulation of Macrophage Phenotype for Therapeutic Revascularization

Tuesday, August 18, 2020

2:00 PM-4:00 PM

BIOMED PhD Research Proposal
Temporal Modulation of Macrophage Phenotype for Therapeutic Revascularization
Gregory Risser, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Kara Spiller, PhD
Associate Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University
Peripheral arterial disease (PAD) occurs when blood vessels narrow, causing loss of blood supply to parts of the body. Blood flow cumulatively decreases in vessels further away from the heart as more and more obstructed vessels are encountered. This cumulative blood flow loss leaves the outer extremities, like the arms and legs, with the least amount of blood. In later stages of PAD, blood flow is almost completely restricted, which can lead to necrosis, gangrene and even amputation of the limb. In these cases, aggressive treatments such as open and endovascular surgery are required. However, these treatments are not safe for higher risk candidates, such as old or diabetic patients. Additionally, 12 to 20% of men and women older than 60 have a form of PAD, underscoring the need for less invasive treatments to promote revascularization of the ischemic tissue for these high-risk patients.

Angiogenesis is the sprouting of blood vessels from preexisting vessels and is a natural mechanism for revascularization. Macrophages, phagocytic innate immune cells, are critical to angiogenesis and tissue remodeling. Therefore, influencing macrophage behavior is a recent strategy to improve angiogenesis in ischemic tissue because macrophages can accomplish many proangiogenic functions with a single treatment. A normal wound undergoes inflammation, then wound healing, followed by tissue resolution. The macrophages present in a wound also follow this progression. Entering the wound as inflammatory (M1) macrophages, they are hypothesized to initiate new blood vessel formation. Macrophages then transition to a pro-healing (M2) phenotype, where they are hypothesized to support the newly formed blood vessels. So, if the natural M1 to M2 macrophage phenotype progression is enhanced, we could potentially increase revascularization of ischemic limbs.

Therefore, this project sets out to improve our understanding of how macrophage phenotype can improve angiogenesis and how timing of macrophage phenotype can play a role. First, we will develop drug delivery microparticles to promote M2 macrophage expression in vitro. Then, using a murine model of acute PAD, we will test the microparticles effectiveness to enhance M2 macrophages supporting blood vessels by delivering the microparticles after a delayed period of time. The delay allows for the initial M1 response on angiogenesis to stimulate new vessel formation. Second, we will test how boosting the initial M1 macrophage response affects angiogenesis by examining endothelial cell behavior such as sprouting and proliferation. Finally, these two methods will be tested in combination with each other to determine how sequentially promoting M1 and then M2 macrophages will help to initiate and support revascularization.

Contact Information

Natalia Broz

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