Current Strategies for the manufacture of Small Size Tissue Engineering Vascular Graft

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

Supporting Remote Maintenance in Industry 4.0 through Augmented Reality

Abstract Due to the Industry 4.0 initiative, Augmented Reality (AR) has started to be considered one of the most interesting technologies companies should invest in, especially to improve their maintenance services. Several technological limitations have prevented AR to become an effective industrial tool in the past. Now some of them have been overcome, some others not yet by off-the-shelf technologies. In this paper, we present a solution for remote maintenance based on off-the-shelf mobile and AR technologies. The architecture of the application allows us to remotely connect a skilled operator in a control room with an unskilled one located where the maintenance task has to be performed. This application, which has been initially described in a previous work, has been improved on the basis of feedback received by industrial partners. We describe the important features we have added and the rationale behind them to make the remote communication more effective

Recent advances in KEAP1/Nrf2-targeting strategies by phytochemical antioxidants, nanoparticles, and biocompatible scaffolds for the treatment of diabetic cardiovascular complications

Abstract Significance: Modulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response is a key aspect in the onset of diabetes-related cardiovascular complications. With this review, we provide an overview of the recent advances made in the development of Nrf2-targeting strategies for the treatment of diabetes, with particular attention toward the activation of Nrf2 by natural antioxidant compounds, nanoparticles, and oxidative stress-modulating biocompatible scaffolds. Recent Advances: In the past 30 years, studies addressing the use of antioxidant therapies to treat diabetes have grown exponentially, showing promising but yet inconclusive results. Animal studies and clinical trials on the Nrf2 pathway have shown promising results, suggesting that its activation can delay or reverse some of the cardiovascular impairments in diabetes. Critical Issues: Hyperglycemia- and oscillating glucose levels-induced reactive oxygen species (ROS) accumulation is progressively emerging as a central factor in the onset and progression of diabetes-related cardiovascular complications, including endothelial dysfunction, retinopathy, heart failure, stroke, critical limb ischemia, ulcers, and delayed wound healing. In this context, accumulating evidence suggests a central role for Nrf2-mediated antioxidant response, one of the most studied cellular defensive mechanisms against ROS accumulation. Future Directions: Innovative approaches such as tissue engineering and nanotechnology are converging toward targeting oxidative stress in diabetes. Antioxid. Redox Signal. 36, 707–72

The Effect of Matrix Stiffness of Biomimetic Gelatin Nanofibrous Scaffolds on Human Cardiac Pericyte Behaviour

Congenital heart disease (CHD) is the most common and deadly congenital anomaly, accounting for up to 7.5% of all infant deaths. Survival in children born with CHD has improved dramatically over the past several decades (this positive trend being counterbalanced by the fact that more patients develop heart failure). Seminal data indicate an alteration of the extracellular matrix occurs with time in these hearts due to diffuse and abundant interstitial fibrosis. This results in an escalation in the stiffness of the local myocardial microenvironment. However, the influence of matrix stiffness in regulating the function of resident human stromal cells has not been reported. The objective of this study was to determine the impact of scaffold stiffness on the antigenic and functional profile of cardiac pericytes (CPs) isolated from patients with CHD. To this end, we have first manufactured gelatin nanofibrous scaffolds with varying degrees of stiffness using an in situ cross-linking electrospinning technique in a pure water solvent system. We assessed Young’s modulus and performed a comprehensive physicochemical characterization of the scaffolds employing scanning electron microscopy and Fourier transform infrared spectroscopy. We next evaluated the changes induced by a different scaffold stiffness on CP morphology, antigenic profile, viability, proliferation, angiocrine activity, and induced differentiation. Results indicate that soft matrixes with a fiber diameter of ∼400 nm increase CP proliferation, secretion of angiopoietin 2, and F-actin stress fiber formation, without affecting the antigenic profile, viability, or differentiation. These data indicate for the first time that human CPs can be functionally influenced by slight changes in matrix stiffness. The study elucidates the importance of mechanical/morphological cues in modulating the behavior of stromal cells isolated from patients with CHD

Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart

Pericytes (PCs) are abundant yet remain the most enigmatic and ill-defined cell population in the heart. Here, we investigated whether PCs can be reprogrammed to aid neovascularization. Primary PCs from human and mouse hearts acquired cytoskeletal proteins typical of vascular smooth muscle cells (VSMCs) upon exclusion of EGF/bFGF, which signal through ERK1/2, or upon exposure to the MEK inhibitor PD0325901. Differentiated PCs became more proangiogenic, more responsive to vasoactive agents, and insensitive to chemoattractants. RNA sequencing revealed transcripts marking the PD0325901-induced transition into proangiogenic, stationary VSMC-like cells, including the unique expression of 2 angiogenesis-related markers, aquaporin 1 (AQP1) and cellular retinoic acid–binding protein 2 (CRABP2), which were further verified at the protein level. This enabled us to trace PCs during in vivo studies. In mice, implantation of Matrigel plugs containing human PCs plus PD0325901 promoted the formation of αSMA(+) neovessels compared with PC only. Two-week oral administration of PD0325901 to mice increased the heart arteriolar density, total vascular area, arteriole coverage by PDGFRβ(+)AQP1(+)CRABP2(+) PCs, and myocardial perfusion. Short-duration PD0325901 treatment of mice after myocardial infarction enhanced the peri-infarct vascularization, reduced the scar, and improved systolic function. In conclusion, myocardial PCs have intrinsic plasticity that can be pharmacologically modulated to promote reparative vascularization of the ischemic heart

Three-Dimensional Printable Enzymatically Active Plastics

[Image: see text] Here, we describe a facile route to the synthesis of enzymatically active highly fabricable plastics, where the enzyme is an intrinsic component of the material. This is facilitated by the formation of an electrostatically stabilized enzyme–polymer surfactant nanoconstruct, which, after lyophilization and melting, affords stable macromolecular dispersions in a wide range of organic solvents. A selection of plastics can then be co-dissolved in the dispersions, which provides a route to bespoke 3D enzyme plastic nanocomposite structures using a wide range of fabrication techniques, including melt electrowriting, casting, and piston-driven 3D printing. The resulting constructs comprising active phosphotriesterase (arPTE) readily detoxify organophosphates with persistent activity over repeated cycles and for long time periods. Moreover, we show that the protein guest molecules, such as arPTE or sfGFP, increase the compressive Young’s modulus of the plastics and that the identity of the biomolecule influences the nanomorphology and mechanical properties of the resulting materials. Overall, we demonstrate that these biologically active nanocomposite plastics are compatible with state-of-the-art 3D fabrication techniques and that the methodology could be readily applied to produce robust and on-demand smart nanomaterial structures

Development of a Novel Hierarchically Biofabricated Blood Vessel Mimic Decorated with Three Vascular Cell Populations for the Reconstruction of Small-Diameter Arteries

The availability of grafts to replace small-diameter arteries remains an unmet clinical need. Here, the validated methodology is reported for a novel hybrid tissue-engineered vascular graft that aims to match the natural structure of small-size arteries. The blood vessel mimic (BVM) comprises an internal conduit of co-electrospun gelatin and polycaprolactone (PCL) nanofibers (corresponding to the tunica intima of an artery), reinforced by an additional layer of PCL aligned fibers (the internal elastic membrane). Endothelial cells are deposited onto the luminal surface using a rotative bioreactor. A bioprinting system extrudes two concentric cell-laden hydrogel layers containing respectively vascular smooth muscle cells and pericytes to create the tunica media and adventitia. The semi-automated cellularization process reduces the production and maturation time to 6 days. After the evaluation of mechanical properties, cellular viability, hemocompatibility, and suturability, the BVM is successfully implanted in the left pulmonary artery of swine. Here, the BVM showed good hemostatic properties, capability to withstand blood pressure, and patency at 5 weeks post-implantation. These promising data open a new avenue to developing an artery-like product for reconstructing small-diameter blood vessels