Development of Multilayer Vascular Grafts Based on Collagen-Mimetic Hydrogels
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Current synthetic vascular grafts have high failure rates in small-diameter (<6 mm) applications due to inadequate cell-material interactions and poor matching of arterial biomechanical properties. To address this, we have developed a multilayer vascular graft design with a non-thrombogenic inner layer that promotes endothelial cell (EC) interactions and a reinforcing layer with tunable biomechanical properties. The blood-contacting layer of the graft is based on a Streptococcal collagen-like protein (Scl2-1). Scl2-1 has the triple helical structure of collagen, but it is a non-thrombogenic protein that can be modified to have selective cell adhesion. For this application, Scl2-2 has been modified from Scl2-1 to contain integrin binding sites that promote EC adhesion. We have developed the methodology to incorporate Scl2 proteins into a poly(ethylene glycol) (PEG) hydrogel matrix. PEG-Scl2 hydrogels facilitate optimization of both bioactivity and substrate modulus to offer unique control over graft endothelialization. However, scaffold properties that promote endothelialization may not be consistent with the mechanical properties necessary to withstand physiological loading. To address this issue, we have reinforced PEG-Scl2-2 hydrogels with an electrospun polyurethane mesh. This multilayer vascular graft design decouples requisite mechanical properties from endothelialization processes and permits optimization of both design goals. We have confirmed the thromboresistance of PEG-Scl2-2 hydrogels in a series of whole blood tests in vitro as well as in a porcine carotid artery model. Additionally, we have shown that the electrospun mesh biomechanical properties can be tuned over a wide range to achieve comparable properties to current autologous grafts. Traditional acrylate-derivatized PEG (PEGDA) hydrogels were replaced with PEG diacrylamide hydrogels with similar properties to increase biostability for long-term implantation. These findings indicate that this multilayer design shows promise for vascular graft applications. As vascular graft endothelialization can significantly improve success rates, the ability to alter cell-material interactions through manipulations in PEG-Scl2-2 hydrogel properties was studied extensively. By reducing Scl2-2 functionalization density and utilizing a biostable PEG functionalization linker, Acrylamide-PEG-I, significantly improved initial EC adhesion was achieved that was maintained over 6 weeks of swelling in vitro. Additionally, increases in Scl2-2 concentration and in hydrogel modulus provided increased EC interactions. It was found that PEG-Scl2-2 hydrogels promoted enhanced EC proliferation over 1 week compared to PEG-collagen gels. In summary, we have developed a vascular graft with a biostable, non-thrombogenic intimal layer that promotes EC adhesion and migration while providing biomechanical properties comparable to current autologous grafts. This design demonstrates great potential as an off-the-shelf graft for small diameter arterial prostheses that improves upon current clinically available options.
Browning, Mary Beth (2013). Development of Multilayer Vascular Grafts Based on Collagen-Mimetic Hydrogels. Doctoral dissertation, Texas A & M University. Available electronically from