Trends in Biotechnology
ReviewNanotechnology in vascular tissue engineering: from nanoscaffolding towards rapid vessel biofabrication
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.
Section snippets
Nanotechnology-based control of cell behavior
Nanotechnology-based approaches in vascular tissue engineering have been used for the design of an instructive extracellular microenvironment for directed cell differentiation and histogenesis 7, 8. The emerging results in this field strongly indicate that nanostructuralized scaffolds and nanopatterned synthetic hydrogels allow control of the vascular cell phenotype 7, 8. The key design parameters that enable the control of cell behavior in biomaterials include ligand identity (specificity),
Nanotechnology in bioengineering of athrombogenicity
The engineering of thromboresistant lumenal surfaces is essential for the maintenance of the patency of implanted tissue-engineered vascular grafts. Three main nanotechnology-based strategies are available for the creation of athrombogenic or thromboresistant lumenal surfaces: (i) the immobilization of athrombogenic molecules and the creation of acellular thromboresistant nanosurfaces [19]; (ii) the immobilization of molecules that have been shown to enhance endothelialization in vitro and in
Nanostructuralized biomimetic vascular scaffolds
Nanostructuralized vascular scaffolds can be fabricated by phase separation, electrospinning and self-assembly of peptides of structural proteins, such as collagen and elastin [27]. The potential advantage of the phase separation method is that it not only allows generation of nanofibers at the same size range as natural ECM collagen but also allows for the design of macropore structures [28], which can enable a more efficient scaffold cellularization with centrifugation [16] or vacuum rotation
Self-assembled collagen and elastin nanofibers
Self-assembly involves the spontaneous organization of individual components into ordered and stable structures of greater complexity. The design of peptide-based fibers, in particular those with a collagen triple helix, which are used as building blocks for self-assembled nanofibers, is a burgeoning field [39]. Collagen is a major structural component in the ECM of the vascular wall, and the creation of novel collagen-based materials that are capable of self-assembly will be an important step
Magnetic-force-driven vascular tissue enginering
It has been shown that functionalized iron oxide nanoparticles can be either attached or incorporated into cells by endocytosis [48] (Figure 2), and the resulting magnetically labeled cells or cell sheets can be driven by magnetic forces to desirable locations. This innovative technology was named magnetic-force-driven tissue engineering 21, 22, 49. There are several possible strategies of magnetic-force-driven tissue assembly for vascular tissue engineering (see Box 1). One approach uses cells
Conclusion
Vascular tissue engineering is one of the ‘Holy Grails’ of tissue engineering. The application of nanotechnology-based approaches in tissue engineering is an emerging and fast-moving research area that has the potential to overcome its currently unsolved problems. The design of athrombogenic lumenal nanosurfaces on vascular grafts and the development of nanostructuralized and nanopatterned biomimicking scaffolds are already well established. The use of nanopatterned functionalized hydrogels for
Acknowledgements
This work was funded by grants from the National Science Foundation (Frontiers in Integrative Biological Research grant EF-0526854) and the Medical University of South Carolina Bioprinting Research Center.
Glossary
- Biofabrication
- the engineering of a tissue assembly.
- Biomimetic
- imitating the structure, organization and functionality of natural tissue.
- Coaxial extruder
- a fluidic device featuring two tubes of different diameters that are placed concentrically, allowing the device to extrude composite or hollow nanofibers.
- Magnetic-force-driven tissue engineering
- biofabrication of more complex tissue constructs using cells, cellular monolayers and cell aggregates labeled with magnetic nanoparticles.
- Nanoparticles
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