# 3D Printing Applied to Tissue Engineered Vascular grafts
###### Abstract  
The broad clinical use of synthetic vascular grafts for vascular diseases is limited by their thrombogenicity and low patency rate, especially for vessels with a diameter inferior to 6 mm. Alternatives such as tissue-engineered vascular grafts (TEVGs), have gained increasing interest. Among the different manufacturing approaches, 3D bioprinting presents numerous advantages and enables the fabrication of multi-scale, multi-material, and multicellular tissues with heterogeneous and functional intrinsic structures. Extrusion-, inkjet- and light-based 3D printing techniques have been used for the fabrication of TEVG out of hydrogels, cells, and/or solid polymers. This review discusses the state-of-the-art research on the use of 3D printing for TEVG with a focus on the biomaterials and deposition methods. 3D printing; bioprinting; additive manufacturing; tissue engineering; blood vessels; vascular grafting +
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platelet activation, migration of smooth muscle cells (SMCs), and production of extracellular matrix, resulting in the thickening of the vessel wall, referred to as intima hyperplasia, and thrombosis. The consequent decrease in graft patency is responsible for vascular failure [3,4]. To address these issues, the development of tissue-engineered vascular grafts (TEVGs) has flourished in recent decades. The next generation of small diameter grafts should present some important improvements. Adequate compliance and mechanical strength that can sustain high pressure and pulsatile flow, optimal anti-thrombotic capacity, and long-term patency are key features that must be addressed. Several strategies for vascular grafts have emerged with a clear preference for biological active multilayer grafts combining cell and biomaterials with a native-like structure. Native vessels are composed of several layers. From the lumen, the first important layer is the endothelium. This monolayer of endothelial cells (ECs) is in direct contact with the blood, provides anti-thrombotic protection, and controls SMC function and homeostasis. The protective layer is challenged by variations in blood flow and pressure. An injured endothelium promotes smooth muscle cell migration and consequent intima hyperplasia. The vessel wall is composed of successive layers of extracellular matrices, SMCs, and fibroblasts. The SMCs regulate the lumen diameter and contractility of the vessel. Oriented layers of elastin and collagen provide the vessels' mechanical properties, such as compliance and strength. Engineering a functional blood vessel relies on the following principles:  
1. A rapid formation of a functional endothelial layer at the surface of the graft increases the hemocompatibility of TEVG by decreasing the occurrence of early thrombosis [5] and late hyperplasia [6]. The endothelialization of the grafts can be achieved either in vitro or in vivo. In vitro, the grafts seeded with ECs are maintained in culture until a functional endothelial monolayer forms. The sources of ECs vary from human autologous ECs, human umbilical vein endothelial cells (HUVECs), stem cell-derived ECs, or CD34\({}^{+}\) endothelial progenitor cells (EPCs). In vivo, endothelialization is promoted by the EPCs recruited into the implanted grafts from the host circulation and/or by the migration of ECs from the adjacent artery. However, to achieve sufficient migration of ECs and recruitment of EPCs, the stimulation of cell adhesion and the use of chemoattractts are important. 2. Both the matrix and the manufacturing process control the structural integrity and mechanical properties (such as burst strength and elastic modulus). As an example, the elastic modulus of a healthy human aorta was reported to be in the range of 1.5 MPa and varies with age and health status [7,8]. In addition, the scaffold design influences cell migration and consequent neotissue formation. In particular, the presence of pores within the scaffolds and their size have been identified as important factors for host cells recruitment.