Formation of a continuous endothelial cell (EC) monolayer inside the luminal surface with enhanced hemocompatibility, is a promising solution for improving performance and overall patency of ...small-diameter vascular grafts. There has been much debate regarding the ideal substrate surface topography to achieve this. Here, we investigated different polycaprolactone (PCL)-derived substrate surfaces fabricated from nanofibers, microfibers, or with smooth surfaces, and evaluated their effect on hemocompatibility and EC behavior. Our results demonstrated that, compared with the other two substrates, smooth surfaces inhibited platelet adhesion and activation, suppressed fibrinogen adsorption, and enhanced EC monolayer formation. In addition, smooth surfaces increased EC nitric oxide (NO) production and acetylated low-density lipoprotein (Ac-LDL) uptake. Thus, we designed and fabricated a bi-layered vascular graft composed of a smooth ultrathin internal layer and a microfibrous external layer, which were capable of preventing spiral-flow and decreasing wall-shear stress. Arterio-venous shunt models revealed that bi-layered grafts avoided bleeding and inhibited both protein absorption and platelet adhesion. Overall, these findings indicated that the prepared bi-layered grafts could perform better for in vivo implantation. Furthermore, this approach doesn't require chemical or biological modifications, and therefore can be easily applied to the fabrication of other implantable tubular grafts using various materials.
Endothelialization and antithrombosis are the keys for small‐diameter vascular grafts to reduce thromboembolism and intimal hyperplasia and achieve revascularization. Nitric oxide (NO) is an ...essential antiplatelet, proendothelialization, and vasodilating agent. Meanwhile, owing to its good biocompatibility, collagen is long considered a feasible material for manufacturing small‐diameter vascular grafts. However, thrombosis and poor mechanical strength remain major drawbacks. A collagen methacrylamide‐co‐selenocysteine (Col‐MA‐Se) composite capable of catalyzing NO release is synthesized here. The Col‐MA‐Se composite improves the blood compatibility of collagen and stimulates the migration and growth of endothelial cells, which suggests that the Col‐MA‐Se composite is suitable for small‐diameter vascular grafts. The prepared composite is then incorporated with polycaprolactone (PCL) to prepare small‐diameter vascular grafts that satisfying basic mechanical requirements for transplantation, followed by a comprehensive exploration of its mechanical strength, endothelial cell response, and platelet behavior. Results confirm the successful construction of collagen/PCL vascular grafts capable of releasing NO and affording rapid endothelialization and antithrombosis, which indicate their promising application prospects for vascular regeneration.
In this study, selenocysteine (SeCA) is successfully coupled with collagen to prepare a collagen methacrylamide‐co‐SeCA (Col‐MA‐Se) composite catalyzing NO release from NO donors into the blood. Small‐diameter vascular grafts that met the mechanical strengths requirement for transplantation are prepared by incorporating polycaprolactone into the Col‐MA‐Se composite. Graft‐catalyzed NO release also promotes the adhesion and proliferation of endothelial cells.
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•Our work provides a new approach to prepare nitric oxide releasing biomaterials.•The approach was based on electrospinning technology and copper-MOF nanoparticles.•The embedding of ...Cu-MOFs within electrospun fibers enhanced its’ stability in serum.•The PCL-MOFs showed long term NO generation ability in vitro and in vivo assays.•The PCL-MOFs exhibited well performances as small diameter vascular grafts in situ.
Copper-MOFs (Cu-MOFs) have been reported to demonstrate great potential as cardiovascular biomaterials, due to enhanced catalytic ability of Cu2+ to generate nitric oxide (NO) from endogenous S-nitrosothiols (RSNOs). However, free Cu-MOFs usually show rapid degradation under physiological conditions, resulting in short catalytic half-life and risk of copper ion toxicity. Therefore, how to increase the stability of Cu-MOFs is of great importance in cardiovascular biomaterials research. Herein, we chose M199 MOF as an example and developed Cu-MOF-based scaffold, using the electrospinning method to embed Cu-MOF nanoparticles into polycaprolactone (PCL) fibers. Entrapment of Cu-MOF nanoparticles within PCL could simultaneously enhance Cu-MOF stability in serum and allow for long-term NO catalytic activity, as assessed by in vitro assays and using in situ implantation models. Additionally, the optimized concentration of Cu-MOFs loaded within the scaffolds significantly promoted endothelial cell (EC) migration and increased acetylated low-density lipoprotein (Ac-LDL) uptake. Moreover, Cu-MOF-based scaffolds dramatically inhibited platelet adhesion and activation, which markedly reduced acute thrombosis in arterio-venous shunt models. In situ implantation experiments revealed that the PCL/Cu-MOF scaffolds accelerated the formation of an intact endothelial monolayer. Together, these results suggest that the incorporation of Cu-MOFs into electrospun fibers could serve as a promising approach to achieve stable catalytic performance and long-term activity required for implant materials.
Tissue Engineering
In article 2205614, Anthony S. Weiss and co‐workers report a nonporous vascular graft from tropoelastin and polyglycerol sebacate that converts into a neoartery, with cellular and ...extracellular matrix structures approximating the native aorta. The resulting neoartery comprises an internal elastic lamina and multiple elastic lamellae sandwiched between circumferentially aligned smooth muscle cell layers. Cover design by Ziyu Wang and illustrated by Ella Maru Studio.
Design and fabrication of scaffolds with three-dimensional (3D) topological cues inducing regeneration of the neo-tissue comparable to native one remains a major challenge in both scientific and ...clinical fields. Here, we developed a well-designed vascular graft with 3D highly interconnected and circumferentially oriented microchannels by using the sacrificial sugar microfiber leaching method. The microchannels structure was capable of promoting the migration, oriented arrangement, elongation, and the contractile phenotype expression of vascular smooth muscle cells (VSMCs) in vitro. After implantation into the rat aorta defect model, the microchannels in vascular grafts simultaneously improved the infiltration and aligned arrangement of VSMCs and the oriented deposition of extracellular matrix (ECM), as well as the recruitment and polarization of macrophages. These positive results also provided protection and support for ECs growth, and ultimately accelerated the endothelialization. Our research provides a new strategy for the fabrication of grafts with the capability of inducing arterial regeneration, which could be further extended to apply in preparing other kinds of oriented scaffolds aiming to guide oriented tissue in situ regeneration.
Globally, millions of patients are affected by myocardial infarction or lower limb gangrene/amputation due to atherosclerosis. Available surgical treatment based on vein and synthetic grafts provides ...sub-optimal benefits. We engineered a highly flexible and mechanically robust nanotextile-based vascular graft (NanoGraft) by interweaving nanofibrous threads of poly-L-lactic acid to address the unmet need. The NanoGrafts were rendered impervious with selective fibrin deposition in the micropores by pre-clotting. The pre-clotted NanoGrafts (4 mm diameter) and ePTFE were implanted in a porcine carotid artery replacement model. The fibrin-laden porous milieu facilitated rapid endothelization by the transmural angiogenesis in the NanoGraft. In-vivo patency of NanoGrafts was 100% at 2- and 4-weeks, with no changes over time in lumen size, flow velocities, and minimal foreign-body inflammatory reaction. However, the patency of ePTFE at 2-week was 66% and showed marked infiltration, neointimal thickening, and poor host tissue integration. The study demonstrates the in-vivo feasibility and safety of a thin-layered vascular prosthesis, viz., NanoGraft, and its potential superiority over the commercial ePTFE.
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•3D-printing was used to prepare TPU vascular grafts loaded with dipyridamole.•TPU samples containing 5% dipyridamole showed antiplatelet properties.•TPU samples containing higher ...drug loadings did not show antiplatelet properties.•The samples showed similar mechanical properties to previously described grafts.•The resulting 3D-printed samples were hemocompatible.•Samples loaded with 5% dipyridamole stimulated HUVEC cell proliferation.
This work describes the use of fused deposition modelling (FDM) to prepare antiplatelet thermoplastic polyurethane (TPU)-based tubular grafts. FDM 3D-printing technology is widely available and provides the ability to easily design tubular grafts on demand, enabling the customisation of vascular prosthesis dimensions. An antiplatelet drug, dipyridamole (DIP), was combined with TPU using hot-melt extrusion to prepare filaments. DIP cargos ranged between 5 and 20% (w/w). The resulting filaments were used to prepare small diameter vascular grafts using FDM. These grafts were characterised. Moreover, DIP release kinetics, antiplatelet activity andin vitrohemo- and cytocompatibility were evaluated. The results suggested that the materialscould providesustained DIP release for 30 days. Moreover, the presence of 5% DIP in the material showed a clear antiplatelet effect compared with pristine TPU. Alternatively, higher DIP loadings resulted higher surface roughness leading to higher platelet adhesion. Therefore, the biocompatibility of 5% DIP samples was tested showing that this type of materials allowed higher HUVEC cell proliferation compared to pristine TPU samples. Finally, DIP loaded TPU was combined with rifampicin-loaded TPU to prepare double-layered tubular grafts. These grafts demonstrated a clear antimicrobial activity against bothStaphylococcus aureusandEscherichia coli.
•By regulating ROS balance and NO production to reduce the inflammation and promote the process of vascular remodeling.•Chelates maintain the catalysis of NO by Cu (Ⅱ) and remove excessive ROS by ...carnosine to reduce adverse effects by Cu (Ⅱ).•Car-Cu (Ⅱ) graft achieved satisfactory effects of anti-thrombotic, anti-inflammatory and pro-endothelialization.
Thrombosis and poor endothelialization of small-diameter vascular grafts (SDVGs) remain the leading cause of frequent failure, despite current tissue-engineered vascular grafts providing a feasible strategy in clinical treatment strategies for the small-diameter (<6 mm) blood vessels in management of cardiovascular disease. Copper ions are normally used to achieve the purpose of antithrombotic because they can produce nitric oxide (NO) with the catalysis of NO donors. However, copper ions also participate in the Fenton reaction to produce reactive oxygen species (ROS), which would adversely affect vascular graft remodeling. Here carnosine, an ion-chelating agent with anti-inflammatory and antioxidant properties, was used to chelate with copper ions to synthesize carnosine-Cu (II) chelate which showed effective activity of antithrombotic, anti-inflammatory, and antioxidant. Besides, our research further demonstrated that copper ions still retain the catalytic activities for producing NO after chelating with carnosine accompanied by the production of lower levels of ROS (the average fluorescence intensity of ROS decreased from 79.69 to 7.13). Furthermore, the grafts achieved excellent patency with satisfactory endothelialization (the endothelial coverage reached 80.64 %) and significantly improved deposition of collagen and glycosaminoglycan for up to 12 weeks. In general, Car-Cu (II) modified SDVGs provided a facile approach to addressing the problems of thrombus and poor endothelialization in SDVGs for the clinic, which is significant in cardiovascular regenerative medicine.
Abstract The vascular grafts prepared by electrospinning often have relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the grafts into ...neoarteries. To overcome this problem, macroporous electrospun polycaprolactone (PCL) scaffolds with thicker fibers (5–6 μm) and larger pores (∼30 μm) were fabricated in the present study. In vitro cell culture indicated that macrophages cultured on thicker-fiber scaffolds tended to polarize into the immunomodulatory and tissue remodeling (M2) phenotype, while those cultured on thinner-fiber scaffolds expressed proinflammatory (M1) phenotype. In vivo implantation by replacing rat abdominal aorta was performed and followed up for 7, 14, 28 and 100 d. The results demonstrated that the macroporous grafts markedly enhanced cell infiltration and extracellular matrix (ECM) secretion. All grafts showed satisfactory patency for up to 100 days. At day 100, the endothelium coverage was complete, and the regenerated smooth muscle layer was correctly organized with abundant ECM similar to those in the native arteries. More importantly, the regenerated arteries demonstrated contractile response to adrenaline and acetylcholine-induced relaxation. Analysis of the cellularization process revealed that the thicker-fiber scaffolds induced a large number of M2 macrophages to infiltrate into the graft wall. These macrophages further promoted cellular infiltration and vascularization. In conclusion, the present study confirmed that the scaffold structure can regulate macrophage phenotype. Our thicker-fiber electrospun PCL vascular grafts could enhance the vascular regeneration and remodeling process by mediating macrophage polarization into M2 phenotype, suggesting that our constructs may be a promising cell-free vascular graft candidate and are worthy for further in vivo evaluation.
Vascular diseases are a major source of fatalities globally. However, the lack of accessibility of autologous vessels and the poor efficacy of commercial small-diameter vascular grafts limit surgical ...alternatives. Researchers therefore aimed to develop vascular prostheses that meet all requirements. Apart from the benefits of tissue-engineered grafts, significant obstacles that still hinder successful grafting include compliance mismatch, dilatation, thrombus development, and the absence of elastin. Among these issues, compliance mismatch between native vessel and artificial vascular scaffold has been mentioned in the literature as a possible cause of intimal hyperplasia, suture site rupture and endothelial and platelet cell damage. As a result, the usage of suitable materials and optimized fabrication techniques are required to achieve better control over the characteristics and functionality of the grafts. In particular, in the case of electrospun vascular grafts, the compliance can be adjusted throughout a broad range of values by adjusting the electrospinning parameters such as material selection, fiber orientation, porosity, and wall thickness. In this study, the electrospun vascular grafts consisting of pure PCL, PLA, and their blends were produced by using two different rotation speeds to achieve the oriented and non-oriented scaffolds. The impact of polymer type and fiber orientation on the compliance properties was evaluated. The results revealed that both material selection and fiber alignment have a significant effect on the compliance levels. PCL100_R grafts had the highest compliance value whereas the PCLPLA50_O scaffold had the lowest.
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