Poly(ethylene glycol)-Based Hydrogels to Support Vascularization and Reendothelialization by Endothelial Colony Forming Cells

Abstract

Endothelial colony forming cells (ECFCs) have a high proliferative capability and can differentiate into endothelial cells, making them a promising cell source for vascularization of ischemic tissues and reendothelialization of injured vasculature. However, it is challenging to deliver the ECFCs to a target site and ensure that their therapeutic functionality is preserved. This research focuses on the development of approaches for subcutaneous and intravascular ECFC delivery with the aid of biomimetic poly(ethylene glycol) (PEG)-based hydrogels. Chapter 1 introduces current treatment for cardiovascular disease (CVD), endothelial cell (EC) sources for treating CVD, and the use of biomaterials to support the functionality of ECs. Chapter 2 describes the development of a microfluidic encapsulation platform that enables rapid production of highly uniform cell-laden hydrogel microspheres, which can be used for numerous applications including supporting injectable cell delivery. Chapter 3 presents the further exploration of the microfluidic platform for production of microspheroids with different geometric shapes, including axial ratio and diameter, and understanding of the underlying mechanism controlling microspheroidal geometry. In chapter 4, autologous equine ECFCs were encapsulated in PEG-fibrinogen hydrogel microspheres using the microfluidic platform and subcutaneously injected into distal limb wounds of horses, demonstrating the feasibility of scalable production of cell-laden microspheres for large animal cell therapy and realization of cell retention and survival after local injection. Results from this study can provide insight on ECFC delivery for vascularization of ischemic tissues for enhancing the wound healing process. In chapter 5, a study investigating the dynamic adhesion of ECFCs on peptide-grafted hydrogels under shear condition is reported. Novel peptide combinations were designed and evaluated for their ability to support ECFC tethering and adhesion. These results can be applied for modification of vascular graft and stent surface for preventing restenosis, which is one of the main long-term causes of failed heart surgery. Overall, new approaches were developed for more efficient delivery of ECFCs subcutaneously and intravascularly to restore blood flow to ischemic tissues.