We propose an approach to use synthetic biomaterial arrays to recruit functional circulating angiogenic cells (CACs), and thereby enhance neovascularization. There is a critical need to: i) systematically explore the biomaterials-associated factors that may be critical to endogenous CAC recruitment, and ii) efficiently discover optimal biomaterials for CAC recruitment and function. We will use an enhanced throughput approach to discover optimal hydrogels for CAC recruitment and sustained function. We propose to use these biomaterials to leverage circulating CACs and enhance angiogenesis in vivo.
Specific Aim 1 will characterize biomaterial parameters that control hCAC invasion and pro-angiogenic function. We hypothesize that the concentration of cell adhesion peptides, biomaterial stiffness, and the identity, dosage, and release rate of soluble chemokines will each significantly influence selective hCAC recruitment and pro-angiogenic function.
Specific Aim 2 will use a novel in vivo hydrogel array to screen optimal biomaterial parameters for hCAC recruitment and hCAC- mediated angiogenesis in a mouse model. We hypothesize that hydrogel arrays implanted into a mouse skin- fold chamber will identify formulations that will improve functional outcome in a subsequent model of hindlimb ischemia. The proposed studies are Significant, as they will enable identification of biomaterials that enhance clinical use of endogenous CACs to improve angiogenesis. Tissue regeneration is limited by poor blood supply, and many disease states (e.g. diabetes) are characterized by a lack of sufficient vasculature. Therefore, a material approach to leverage endogenous CACs could have a substantial impact on tissue regeneration approaches. The proposed studies are Innovative, as they use chemically-defined hydrogel arrays to discover biomaterial cues for selective CAC recruitment and function, both in vitro and in vivo. The arrays are composed of biomaterials that are highly adaptable, such that the biochemical and biophysical properties of array spots can be broadly varied. These studies will provide a basis for a larger research program to elucidate the mechanisms of endogenous cell recruitment and CAC-mediated angiogenesis in vitro and in vivo.
Insufficient neovascularization is often the cause of poor clinical outcome during wound healing, and remains one of the foremost challenges in tissue engineering and regenerative medicine. Many strategies have been designed to induce neovascularization in healing tissues, including delivery of pro-angiogenic proteins and pro- angiogenic cells. However, clinical strategies have not yet achieved a high level of efficacy for treatment of ischemic conditions. A compelling approach to this problem involves delivery of circulating angiogenic cells (CACs), which can secrete multiple pro-angiogenic cues that induce neovascularization at sites of tissue damage. Recent CAC delivery strategies have demonstrated some efficacy for treatment of coronary artery disease, myocardial ischemia, and myocardial infarction, and CAC delivery is also being used to treat diabetic wounds and large bone defects. Taken together, these studies suggest that CAC delivery is a promising clinical approach. However, clinical applications of CACs are limited by low prevalence in blood and challenging regulatory approval for strategies that involve ex vivo cell manipulation. We propose an approach to discover materials that optimally recruit functional CACs already present in the human bloodstream. Our proposed approach to leverage endogenous CACs could have a substantial impact on treatments of diseases (e.g. diabetes, coronary artery disease), as well as emerging tissue regeneration schemes.
