Tissue-engineered vascular grafts (TEVGs) show great potential in clinics for treating vascular diseases. However, the complications including thrombosis, delayed endothelialization, and ...endothelial-to-mesenchymal transition (EndMT) induced pathological remodeling have been demonstrated to be the main cause of graft failure. Here, we have developed a multifunctional surface by immobilizing ALK5 inhibitor loaded covalent organic framework (COF) nanoparticles, recombinant CD47 protein, and vascular endothelial growth factor (VEGF). Such a surface can prevent thrombosis and stenosis in TEVGs. Immobilization of VEGF facilitated the recruitment of endothelial-forming cells to accelerate endothelialization. Grafting of CD47 endowed the TEVGs with stealth function to inhibit the adhesion and activation of platelets and macrophages, thereby suppressing thrombus formation and reducing the secretion of EndMT triggers (i.e. TNF-α and IL-1β). In addition, long-term in situ delivery of ALK5 inhibitor could block the TGF-β signaling pathway that mediated EndMT to prevent intima hyperplasia and endothelial dysfunction during graft remolding. This synergistic strategy is competent to support the formation of functional endothelium on the neo-intima, and has shown promising preliminary results in keeping the patency of TEVGs.
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•Co-immobilization of CD47, VEGF, and ALK5 inhibitor loaded COF nanoparticles created a multifunctional surface on TEVGs.•Immobilization of CD47 possesses excellent ability to prevent the adhesion and activation of platelets and macrophages.•VEGF grafting accelerated endothelialization by homing endothelial forming cells.•In situ delivery of ALK5 inhibitor prevented the EndMT induced pathological remodeling of the TEVGs.•The TEVGs has high patency without thrombosis and stenosis.
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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.
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•A novel biocompatible, hemocompatible, and mechanically strong bi-layered small-diameter vascular graft was designed.•The bio-inspired design and careful selection of materials can ...improve the endothelialization without loading drug molecules.•Conclusively, the graft could be an affordable and accessible option in the field of small-diameter vessel reconstruction.
Despite the tremendous advances in the past few decades, the clinical problems associated with low mechanical strength, thrombosis, and inadequate endothelialization still have not been improved in small diameter vascular grafts. The objective of this study is to design and fabricate a dual layered small-diameter vascular graft by electrospinning process which will mechanically and biologically match the gold standard of blood vessel substitution. The presented graft was composed of polycaprolactone/gelatin (inner layer) and polyurethane/polycaprolactone (outer layer) and fabricated by sequential electrospinning process. Physico-mechanical evaluation, in vitro biocompatibility and hemocompatibility assays were performed for both layers to ensure safe in vivo applications Then, the vascular grafts were successfully implanted into a rat abdominal aorta model. Tubular vascular graft had a nanofibrous and porous outer structure, which provided a conducive micro-environment for smooth muscle cell migration as well as proliferation but the lumen wall had a smooth surface to reduce thrombogenicity and improve endothelialization. Both layers showed excellent biocompatibility and hemocompatibility in all in vitro assays. After three months, the harvested grafts exhibited smooth muscle cell regeneration and complete endothelialization on the graft lumen. The dual layered graft could therefore play a pivotal role in the arena of vascular tissue regeneration application.
Modeling the processes of neuronal progenitor proliferation and differentiation to produce mature cortical neuron subtypes is essential for the study of human brain development and the search for ...potential cell therapies. We demonstrated a novel paradigm for the generation of vascularized organoids (vOrganoids) consisting of typical human cortical cell types and a vascular structure for over 200 days as a vascularized and functional brain organoid model. The observation of spontaneous excitatory postsynaptic currents (sEPSCs), spontaneous inhibitory postsynaptic currents (sIPSCs), and bidirectional electrical transmission indicated the presence of chemical and electrical synapses in vOrganoids. More importantly, single-cell RNA-sequencing analysis illustrated that vOrganoids exhibited robust neurogenesis and that cells of vOrganoids differentially expressed genes (DEGs) related to blood vessel morphogenesis. The transplantation of vOrganoids into the mouse S1 cortex resulted in the construction of functional human-mouse blood vessels in the grafts that promoted cell survival in the grafts. This vOrganoid culture method could not only serve as a model to study human cortical development and explore brain disease pathology but also provide potential prospects for new cell therapies for nervous system disorders and injury.
Nanofiber vascular grafts have been shown to create neovessels made of autologous tissue, by in vivo scaffold biodegradation over time. However, many studies on graft materials and biodegradation ...have been conducted in vitro or in small animal models, instead of large animal models, which demonstrate different degradation profiles. In this study, we compared the degradation profiles of nanofiber vascular grafts in a rat model and a sheep model, while controlling for the type of graft material, the duration of implantation, fabrication method, type of circulation (arterial/venous), and type of surgery (interposition graft). We found that there was significantly less remaining scaffold (i.e., faster degradation) in nanofiber vascular grafts implanted in the sheep model compared with the rat model, in both the arterial and the venous circulations, at 6 months postimplantation. In addition, there was more extracellular matrix deposition, more elastin formation, more mature collagen, and no calcification in the sheep model compared with the rat model. In conclusion, studies comparing degradation of vascular grafts in large and small animal models remain limited. For clinical translation of nanofiber vascular grafts, it is important to understand these differences.
Several patient groups undergoing small‐diameter (<6 mm) vessel bypass surgery have limited autologous vessels for use as grafts. Tissue‐engineered vascular grafts (TEVG) have been suggested as an ...alternative, but the ideal TEVG remains to be generated, and a systematic overview and meta‐analysis of clinically relevant studies is lacking. We systematically searched PubMed and Embase databases for (pre)clinical trials and identified three clinical and 68 preclinical trials (>rabbit; 873 TEVGs) meeting the inclusion criteria. Preclinical trials represented low to medium risk of bias, and binary logistic regression revealed that patency was significantly affected by recellularization, TEVG length, TEVG diameter, surface modification, and preconditioning. In contrast, scaffold types were less important. The patency was 63.5%, 89%, and 100% for TEVGs with a median diameter of 3 mm, 4 mm, and 5 mm, respectively. In the group of recellularized TEVGs, patency was not improved by using smooth muscle cells in addition to endothelial cells nor affected by the endothelial origin, but seems to benefit from a long‐term (46–240 hours) recellularization time. Finally, data showed that median TEVG length (5 cm) and median follow‐up (56 days) used in preclinical settings are relatively inadequate for direct clinical translation. In conclusion, our data imply that future studies should consider a TEVG design that at least includes endothelial recellularization and bioreactor preconditioning, and we suggest that more standard guidelines for testing and reporting TEVGs in large animals should be considered to enable interstudy comparisons and favor a robust and reproducible outcome as well as clinical translation.
Systematic meta‐analysis of large animal studies testing patency of tissue‐engineered vascular grafts show that tissue‐engineered vascular graft surface modification, preconditioning, and recellularization increase patency, whereas an increasing graft length and a decreasing diameter decrease patency. Importantly, the scaffold type, endothelial origin, and the addition of smooth muscle cells do not have an immediate effect on tissue‐engineered vascular graft patency.
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•Double-layer TENG intended for self-powered and real-time sensing was constructed.•The open-circuit voltage and power density of the TENG were 440 V and 1877 mW/m2.•The ePTFE/PHB ...TENG was capable of supporting the HUVECs adhesion and growth.•The ePTFE/PHB TENG could effectively monitor the changing hemodynamic conditions.•The ePTFE/PHB TENG vascular counterpart exhibited excellent pressure sensitivity.
Being able to detect or monitor the onset of thrombosis, recurrent stenosis, or other vascular disorders in newly transplanted vascular grafts will be very beneficial for patients who received the artificial blood vessel through bypass surgeries. The inherent advantages of triboelectric nanogenerators (TENGs) in self-powered signal monitoring presents a feasible solution. In this study, a double-layer TENG intended for self-powered and real-time sensing of vascular graft applications was constructed using two biocompatible materials commonly used in tissue engineering. In particular, an electrospun poly(3-hydroxybutyrate) (PHB) membrane as a positive tribomaterial was combined with an expanded polytetrafluoroethylene (ePTFE) membrane, a strong negative tribomaterial, to construct an ePTFE/PHB TENG. While possessing power generation, charging capacities, and operation stability, the ePTFE/PHB TENG was capable of supporting the growth of human umbilical vein endothelial cells (HUVECs) and monitoring changing hemodynamic conditions. Although many challenges remain and necessary future developments are needed, this study demonstrated the feasibility of a self-powered and sensing TENG vascular graft.
Abstract Current limitations of exogenous scaffolds or extracellular matrix based materials have underlined the need for alternative tissue-engineering solutions. Scaffolds may elicit adverse host ...responses and interfere with direct cell–cell interaction, as well as assembly and alignment of cell-produced ECM. Thus, fabrication techniques for production of scaffold-free engineered tissue constructs have recently emerged. Here we report on a fully biological self-assembly approach, which we implement through a rapid prototyping bioprinting method for scaffold-free small diameter vascular reconstruction. Various vascular cell types, including smooth muscle cells and fibroblasts, were aggregated into discrete units, either multicellular spheroids or cylinders of controllable diameter (300–500 μm). These were printed layer-by-layer concomitantly with agarose rods, used here as a molding template. The post-printing fusion of the discrete units resulted in single- and double-layered small diameter vascular tubes (OD ranging from 0.9 to 2.5 mm). A unique aspect of the method is the ability to engineer vessels of distinct shapes and hierarchical trees that combine tubes of distinct diameters. The technique is quick and easily scalable.
Tissue‐engineered blood vessel substitutes have been developed due to the lack of suitable small‐diameter vascular grafts. Xenogeneic extracellular matrix (ECM) scaffolds have the potential to ...provide an ideal source for off‐the‐shelf vascular grafts. In this study, porcine carotid arteries were used to develop ECM scaffolds by decellularization and coating with heparin and hepatocyte growth factor (HGF). After decellularization, cellular and nucleic materials were successfully removed with preservation of the main compositions (collagen, elastin, and basement membrane) of the native ECM. The ultimate tensile strength, suture strength, and burst pressure were significantly increased after cross‐linking. Pore size distribution analysis revealed a porous structure within ECM scaffolds with a high distribution of pores larger than 10 μm. Heparinized scaffolds exhibited sustained release of heparin in vitro and showed potent anticoagulant activity by prolonging activated partial thromboplastin time. The scaffolds showed an enhanced HGF binding capacity as well as a constant release of HGF as a result of heparin modification. When implanted subcutaneously in rats, the modified scaffolds revealed good biocompatibility with enzyme degradation resistance, mitigated immune response, and anti‐calcification. In conclusion, heparinized and HGF‐coated acellular porcine carotid arteries may be a promising biological scaffold for tissue‐engineered vascular grafts.
To achieve long-term patent small-diameter (<6 mm) vascular implants, biomimetic vascular grafts have gained much attention in promoting in situ blood vessel regeneration. In this study, ...hierarchical-structured bacterial cellulose/potato starch (BC/PS) composites were biosynthesized by the addition of swollen PS. Investigations on the physicochemical properties of BC/PS composites showed that the properties could be improved and tailored by the addition of swollen PS. The composites displayed a morphology, water content, thermal properties, mechanical properties, and biocompatibility appropriate for vascular tissue engineering. Most importantly, the BC/PS grafts, with a dense inner surface and a circumferential macroporous outer layer, possessed 75% patency and promoted rapid blood vessel regeneration in in vivo assessment on rabbits, with complete endothelium monolayer, organized smooth muscle cells, rich new capillaries, and deposited extracellular matrix. Collectively, these findings demonstrate that hierarchical-structured BC/PS tubes hold great promise as artificial small-diameter vascular grafts.
•The BC/PS vascular graft showed a hierarchical-structure with small diameter (1 mm).•The BC/PS possessed excellent physicochemical properties and biocompatibility.•The BC/PS vascular graft induced rapid blood vessel regeneration with high patency.
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