Nanotechnology in vascular tissue engineering: from nanoscaffolding towards rapid vessel biofabrication

The existing methods of biofabrication for vascular tissue engineering are still bioreactor-based, extremely expensive, laborious and time consuming and, furthermore, not automated, which would be essential for an economically successful large-scale commercialization. The advances in nanotechnology can bring additional functionality to vascular scaffolds, optimize internal vascular graft surface and even help to direct the differentiation of stem cells into the vascular cell phenotype. The development of rapid nanotechnology-based methods of vascular tissue biofabrication represents one of most important recent technological breakthroughs in vascular tissue engineering because it dramatically accelerates vascular tissue assembly and, importantly, also eliminates the need for a bioreactor-based scaffold cellularization process.

Introduction

Since the classic work of Eugene Bell two decades ago [1], the field of vascular tissue engineering has gradually evolved into a well established and intensively researched area of biotechnology. Moreover, recent reports on the successful clinical implantation of tissue-engineered blood vessels by the US company Cytograft Tissue Engineering Inc. 2, 3 is an important historic milestone in the development of vascular tissue engineering. However, currently employed engineering processes for vascular tissue remain bioreactor-based and thus are extremely expensive, laborious, time consuming and non-automated. It is becoming increasingly obvious from the history of bankruptcy of first generation tissue engineering companies that a successful commercialization of vascular-tissue-engineered products can only be achieved when rapid, automated and cost-effective methods for tissue assembly and large-scale biofabrication are employed.

To perform sufficiently, the ideal tissue-engineered vascular graft must fulfill several requirements. The graft needs to be covered by athrombogenic endothelial cells and be resistant to thrombosis. It should also have comparable biomechanical properties and be able to resist a narrowing of the lumen by intimal thickening, which could have serious consequences, such as loss of graft patency, proteolytic degradation of extracellular matrix (ECM) and development of degradation-associated vascular dilation or aneurysm 4, 5, 6. Thus, the prevention of thrombosis, vascular intimal thickening and aneurysm is essential for the successful post-implantational functioning and long-term patency of a tissue-engineered vascular graft. Three approaches have been well established for tissue assembly in vascular tissue engineering: (i) a solid-scaffold-based approach that involves cell seeding into a porous solid scaffold; (ii) a hydrogel-based approach in which cells are embedded in a hydrogel; and (iii) a cell-sheet-based assembly approach that involves the rolling of cohesive cell monolayers 4, 5, 6.

Nanotechnology creates new platforms that might enable novel tissue-engineering technologies. Although by definition nanotechnology deals with objects in the range of 1 to 100 nm, even large tissue-engineered blood vessels can be constructed from nanostructuralized and nanopatterned biomaterials [6]. For example, nanopatterns on the surface of a vascular graft with nanofilms can reduce its athrombogeneity or increase its adhesiveness for circulating endothelial progenitor cells. Nanostructuralized scaffolding can mimic the organization of a natural vascular ECM and thus improve cell attachment [6]. Hydrogels have been modified with nanopatterned growth factors and ECM peptides, which brought additional functionalities and improved the capacity of the hydrogel to direct cell and tissue differentiation 7, 8. It is important to mention that all classic vascular-tissue-engineering approaches require the long-term placement and conditioning of the vascular-tissue-engineered constructs in perfusion bioreactors to obtain functional tissues. In this context, the development of nanotechnology-based rapid and bioreactor-free methods of vascular tissue biofabrication described below could eliminate the need for expensive and time consuming bioreactor-based processes, such as scaffold cellularization and tissue maturation [6]. In this review we present such emerging nanotechnology-based approaches in tissue engineering and discuss how nanotechnology can enable vascular tissue engineering.