Current Strategies for the Manufacture of Small Size Tissue Engineering Vascular Grafts

Abstract

Occlusive arterial disease, including coronary heart disease (CHD) and peripheral arterial disease (PAD), is the main cause of death, with an annual mortality incidence predicted to rise to 23.3 million worldwide by 2030. Current revascularization techniques consist of angioplasty, placement of a stent, or surgical bypass grafting. Autologous vessels, such as the saphenous vein and internal thoracic artery, represent the gold standard grafts for small-diameter vessels. However, they require invasive harvesting and are often unavailable. Synthetic vascular grafts represent an alternative to autologous vessels. These grafts have shown satisfactory long-term results for replacement of large- and medium-diameter arteries, such as the carotid or common femoral artery, but have poor patency rates when applied to small-diameter vessels, such as coronary arteries and arteries below the knee. Considering the limitations of current vascular bypass conduits, a tissue-engineered vascular graft (TEVG) with the ability to grow, remodel, and repair in vivo presents a potential solution for the future of vascular surgery. Here, we review the different methods that research groups have been investigating to create TEVGs in the last decades. We focus on the techniques employed in the manufacturing process of the grafts and categorize the approaches as scaffold-based (synthetic, natural, or hybrid) or self-assembled (cell-sheet, microtissue aggregation and bioprinting). Moreover, we highlight the attempts made so far to translate this new strategy from the bench to the bedside.

Keywords: myocardial ischemia; regenerative medicine; stem cells; tissue engineering; vascular conduits.

Figure 1

Schematic illustration of TEVG manufacturing process. (A,B) Tissues obtained from biopsies of patients are treated and cells are isolated and expanded in vitro. (C) Microfabrication techniques, such as freeze-drying and electrospinning, can be used to treat natural and synthetic materials in order to obtain a porous scaffold. Another approach sees the casting of a suspension of gel and cells into a mold to produce a tubular structure. Vascular and non-vascular tissues, obtained from allogeneic or xenogeneic sources, are used as TEVGs after being decellularized by using detergents and enzymes. (D) The TEVG undergoes cellularization with the expanded autologous cells before moving to dynamic conditioning into bioreactor which allows the maturation of the structure. (E) The manufactured TEVG is implanted into the patient.

Figure 2

Schematic representation of techniques to manufacture scaffold-free vascular grafts. (A) Cell-sheet TEVG approach involves the use of a dense and cohesive sheet of cells to create a tubular structure. The sheet is rolled around a mandrel and matured under dynamic conditions to develop vessel-like properties. (B) Hanging drop cells are accurately positioned into a mold in the microtissue aggregation approach (B). The production of ECM allows the merging of the aggregates in a complex structure. (C) Bioprinting exploits the extrusion of support material to increase the flexibility of the fabrication. An accurate design of support material and cells extruded in spheroids allows the creation of tubular structures.