Collagen biomaterials for the delivery of FVIII-producing blood outgrowth endothelial cells in the treatment of Haemophilia A

Abstract

In this thesis, we describe the fundamental aspects to the development of molecularly-defined tailor-made scaffolds for the delivery of FVIII-expressing endothelial cells in the treatment of Haemophilia A. In particular, scaffolds prepared by chemical crosslinking of type I collagen, and growth factor incorporation is discussed. The general strategy was to prepare tailor-made biomaterials as a specific microenvironment to enable cells to produce FVIII and secrete this coagulation factor into the blood stream. As an initial step, pure materials of known concentrations were combined to develop two forms of collagen scaffolds: an injectable hydrogel that may be formed in situ in the presence of cells and a capsule into which the cell-housing hydrogel can be injected. Next, scaffolds were crosslinked using natural- genipin- and synthetic- carbodiimide (EDC)- chemicals. Crosslinking resulted in collagenase-resistant scaffolds. The tissue response to scaffolds was evaluated following subcutaneous implantations in mice. Crosslinked scaffolds maintained their integrity and supported the formation of new extracellular matrix and neovascularization during tissue remodeling. Collagen scaffolds loaded with fibroblast growth factor 2 significantly enhanced FVIII production during long-term encapsulation. Potential applications of these scaffolds for ischemic models are discussed in more detail.