Long-term results of triple-layered small diameter vascular grafts in sheep carotid arteries
Graphical abstract
Introduction
There has been a significant increase in the demand for small-diameter vascular grafts (SDVGs, with inner diameters less than 6 mm) owing to the increasing incidence of atherosclerotic vascular disease [1,2]. Autologous blood vessels are commonly used for vascular bypass transplantation to avoid the risk of immune rejection. However, low availability and secondary trauma to the patient limit their applications [3]. Commercial DacronⓇ or expanded poly-tetrafluoroethylene vascular grafts have been successfully applied as substitutes of large-diameter blood vessels (with inner diameters exceeding 6 mm) [4]. Unfortunately, they have failed to replace small-diameter vessels owing to the high frequency of intimal hyperplasia and thrombosis [5].
To achieve long-term patency of SDVGs, the material make-up and structure of the grafts play an important role [6,7]. Biodegradable SDVGs have received increasing attention because they have the potential to restore vascular function with the degradation of vascular graft and tissue regeneration [8]. Biodegradable synthetic polymers, such as polycaprolactone, poly l-lactic acid, polyurethane (PU), poly lactic-co-glycolic acid, and poly glycerol sebacate, have recently been intensively used in medical applications [9]. Among them, thermoplastic polyurethane (TPU) has been widely applied to fabricate biodegradable vascular grafts owing to its superior mechanical strength, biocompatibility, and flexibility [7,10].
Furthermore, the structure of vascular grafts is critical to mimicking the function of native arteries. It is demonstrated that natural artery walls are comprised of three layers: intima, media, and adventitia. More specifically, the intima, or inner layer, is composed of a continuous monolayer of vascular endothelial cells; the media, or middle layer, consists of a dense population of vascular smooth muscle cells; the adventitia, or outer layer, mainly contains fibroblasts and perivascular nerve cells [11]. It is worth mentioning that a common problem with vascular grafts is that they have a small pore size, which usually leads to insufficient cell infiltration [12]. Accordingly, designing a multi-layered vascular graft and regulating the structure of each layer by adjusting the pore size and porosity is an effective method to mimic native blood vessels.
Thus far, published evaluations of vascular grafts in vivo have a few limitations associated with the animal models used and the implantation period observed [13]. Small animals, such as mice and rabbits, are not suitable for long-term in vivo hemodynamic studies because their physiology is unlike that of humans. Generally, large animal models such as those of sheep, goats or pigs are more suited for long-term evaluation [14,15]. However, a majority of the studies on grafts implanted in larger animal have been accomplished within weeks or at the most several months [13]. Therefore, in this study, we focus on the fabrication, characterization, and in vivo evaluation of triple-layered TPU SDVGs for a period of up to 12 months, using a sheep carotid arterial replacement model.
Section snippets
Materials
TPU and polyvinyl alcohol (PVA) filaments were supplied by Shenzhen Guanghua Weiye Industrial Co. Ltd., China. Tetrahydrofuran (THF) was purchased from Beijing Chemical Works, China.
Fabrication of the vascular grafts
TPU granulates were dissolved in THF to prepare 10% wt. TPU solution; thereafter, ground NaCl particles were added into TPU solution. The solution was magnetically stirred for 12 h to accelerate dissolution. A sacrificial core-coating forming technique was employed in this study, as reported in a previous work [16].
Graft fabrication and characterization
Natural artery walls are comprised of three layers. Among them, the middle layer is the thickest layer in arteries, and mechanical properties of blood vessels, such as elasticity and compliance, mainly depend on the middle layer. Inspired by the three-layer structure of native blood vessels, we designed triple-layered SDVGs, with each layer executing the role of a distinct structure. Figure 2(a) and 2(b) show that the prepared SDVGs exhibit a smooth surface without any gross defects and that
Discussion
SDVGs with adequate physical structure and sufficient biological activity have the potential to achieve complete vascularization functionality. However, the realization of this goal still poses an intricate challenge, particularly in the area of vascular tissue engineering [20]. Cell infiltration is a fundamental and essential requirement for vascular regeneration and extracellular matrix (ECM) secretion [21]. Subsequently, from a long-term point of view, angiogenesis and remodeling of vascular
Conclusions
Triple-layered SDVGs were designed to mimic native blood vessels, in which the inner and outer layer with porous structure serve as functional layers for cell adhesion and proliferation, and the thick middle layer serves as a structural layer which provides sufficient strength. Here we evaluated triple-layered SDVGs in a sheep carotid arterial replacement model. Following implantation in vivo for 12 months, grafts exhibited better degradation and cell infiltration. Two cases suggested the
Funding
This work was supported by the Beijing Municipal Science and Technology Commission (Z141100000214012).
Ethical approval
All animal procedures were performed under institutional guidelines for animal care and approved by the Animal Ethics Committee of Fuwai Hospital (Beijing, China).
Declaration of Competing Interest
None declared.
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