Small-diameter Blood Vessels Research Articles

Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property.

Polymers that are biocompatible and degradable are desired for tissue engineering approaches in the treatment of vascular diseases, especially for those involving small-diameter blood vessels. Herein, we report the compatibility of a newly developed glycerol-based aliphatic polycarbonate possessing simple methoxy side groups, named poly(5-methoxy-1,3-dioxan-2-one) (PMDO), with blood cells and plasma proteins as well as its susceptibility to hydrolysis. As a consequence of the organocatalytic ring-opening polymerization (ROP) of a methoxy-functionalized cyclic carbonate derived from glycerol, PMDO with a sufficiently high molecular weight (Mn 14 kg/mol) and a narrow distribution (D̵M 1.12) was obtained for evaluation as a bulk biomaterial. This study demonstrates for the first time the organocatalytic ROP of a glycerol-based cyclic carbonate in a controlled manner. Compared with the clinically applied aliphatic polycarbonate poly(trimethylene carbonate) (PTMC), PMDO inhibits platelet adhesion by 33% and denaturation of fibrinogen by 23%. Although the wettability of PMDO based on water contact angle was almost comparable to those of PTMC and poly(ethylene terephthalate), the reason for the inhibited platelet adhesion and protein denaturation appeared to be related to the presence of specific hydrated water formed in the hydrated polymer. The improved hydration of PMDO also enhanced the susceptibility to hydrolysis, with PMDO demonstrating a slightly higher hydrolytic property than PTMC. This simple glycerol-based aliphatic polycarbonate has the following benefits: bio-based characteristics of glycerol and improved blood compatibility and hydrolytic biodegradability stemming from moderate hydration of the methoxy side groups.

Biorheological Model on Pulsatile Flow of Blood (K–L Fluid) Through Flexible Stenotic Tapered Blood Vessels

In the present article, we investigate the pulsatile flow of blood through a tapered constricted blood vessel with a flexible nature of the wall and no-slip condition on the wall in view of analyzing the role of rheological behavior of blood, flow amplitude, the flexibility of wall, tapering, stenotic shape, and height in the origination and proliferation of cardiovascular disorders. The rheology of blood is treated as viscous incompressible non-Newtonian Luo and Kuang (K–L) model fluid by taking into account that the influence of non-Newtonian nature of blood with a finite yield stress and shear thinning character when it flows in small-diameter blood vessels. The pressure gradient has been taken as a periodic function of time, which accounts for the effects of systole and diastole of the heart. The equations governing the flow of K–L fluid when the stenotic vessel is slightly tapered are coupled and highly non-linear. A standard perturbation technique is adopted to solve the equations subject to the suitable boundary conditions assuming that the pulsatile Reynolds number is small, which is valid for physiological conditions in small blood vessels. The analytical expressions for flow characteristics, namely, the blood velocity distribution, the plug-core radius, the volumetric flow flux, the wall shear stress, and the impedance have been obtained by considering three terms (the coefficients of $$\alpha ^0, \alpha ^2,$$ and $$\alpha ^4$$ ) in the flow characteristics for the first time. The influence of physiologically vital parameters such as pulsatile Reynolds number, the amplitude of the flow, yield stress, K–L fluid parameters, time, amplitude constant, shape parameter of the constriction, maximum height of the constriction, and the tapering parameter on the flow variables are investigated, and the results are depicted graphically using MATLAB software. From the analysis, it is noticed that the yield stress, K–L fluid parameters, tapering angle, and the flexibility of the vessel wall have a substantial impact on examining the blood flow through tapered blood vessels with time-dependent constriction. The wall shear stress and resistive impedance increase as the K–L fluid parameters, yield stress, stenotic height increase, and decrease with the increase in Womersley frequency parameter, flow amplitude, and time-variant parameter.

Tissue Engineered Bovine Saphenous Vein Extracellular Matrix Scaffolds Produced Via Antigen Removal Achieve High <i>In Vivo</i> Patency Rates

Diseases of small diameter blood vessels encompass the largest portion of cardiovascular diseases, with over 4.2 million people undergoing autologous vascular grafting every year. However, approximately one third of patients are ineligible for autologous vascular grafting due to lack of suitable donor vasculature. Acellular extracellular matrix (ECM) scaffolds derived from xenogeneic vascular tissue have potential to serve as ideal biomaterials for production of an off-the-shelf vascular graft capable of eliminating the need for autologous vessel harvest. Using the antigen removal tissue processing method an off-the-shelf small diameter (< 3 mm) vascular graft from bovine saphenous vein was produced with significantly reduced antigenic content, while retaining the structure and function of its native vascular ECM proteins. Elimination of native tissue antigen content conferred graft-specific adaptive immune avoidance. Retention of native ECM protein macromolecular structure, as assessed by collagen polarization, resulted in pro-regenerative cellular infiltration, ECM turnover and innate immune self-recognition. Finally, retention of the delicate vascular basement membrane protein integrity conferred endothelial cell repopulation and 100% patency rate in a rabbit jugular interposition model, comparable only to Autograft implants. Alternatively, the lack of these important basement membrane proteins in otherwise identical scaffolds yielded a patency rate of only 20%. We conclude that acellular antigen removed bovine saphenous vein ECM scaffolds have potential to serve as ideal off-the-shelf small diameter vascular scaffolds with high in vivo patency rates due to their low antigen content, retained native tissue basement membrane integrity and preserved native ECM structure, composition and functional properties.

Thick PCL Fibers Improving Host Remodeling of PGS-PCL Composite Grafts Implanted in Rat Common Carotid Arteries.

Vasculopathy and the consequential ischemia are major medical challenges. Grafting is an effective treatment to vascular occlusion. However, autologous grafting, despite scarcity, is the only choice for small diameter blood vessels. Synthetic grafts can fill the gap if they can work satisfactorily in arterial circulation. Electrospun polycaprolactone (PCL) sheathed porous poly(glycerol sebacate) (PGS) vascular grafts have good performances in arterial circulation in abdominal aortas and carotid arteries in rats. However, a major issue associated with the graft remodeling in vivo is limited neo-tissue formation inside PCL sheaths. Small pores of PCL sheaths inhibit cell infiltration and migration. To increase porosity of PCL sheaths of PGS-PCL composite grafts, diameters of electrospun PCL fibers are increased. The thick PCL fibers encourage cell migration and elicit a higher degree of CD206+ cells. In addition, some of the CD206+ cells co-express vascular cell markers in the thick-fiber grafts. The thick-fiber grafts also show improved mechanical properties and a higher elastin and collagen content. The data demonstrate the feasibility of improving graft vascular remodeling by increasing PCL fiber diameters and the critical role of CD206+ cells during graft vascular remodeling.

Assessment of conbercept therapy for high myopia macular neovascularization by optical coherence tomography angiography

This study aimed to evaluate the efficacy and safety of the intravitreal injection of conbercept in the treatment of macular neovascularization (MNV) secondary to high myopia and to observe the application of optical coherence tomography angiography (OCTA) in the treatment follow-up. We reviewed the medical records of 20 patients (21 eyes) with MNV secondary to high myopia who were enrolled in the Department of Ophthalmology of the First Hospital of China Medical University between May 2018 and January 2020. Each patient received one or more intravitreal injections of conbercept (0.5 mg/0.05 mL). The treatment was conducted according to a 1 + PRN (pro re nata) regimen. The changes of best corrected visual acuity (BCVA), central macular thickness (CMT), and selected MNV and flow areas measured by OCTA were observed over a 6-month follow-up period. The mean logarithm of the minimum angle of resolution (logMAR) BCVA was 1.03 ± 0.61 before treatment and improved to 0.83 ± 0.59 (P = 0.007), 0.78 ± 0.62 (P = 0.001), 0.81 ± 0.73 (P = 0.027), and 0.79 ± 0.72 (P = 0.023) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. The mean CMT was 358.16 ± 206.11 μm before treatment and decreased to 295.38 ± 178.70 μm (P = 0.003), 288.34 ± 165.60 μm (P = 0.004), 284.36 ± 163.07 μm (P = 0.005), and 283.00 ± 160.32 μm (P = 0.004) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. Nineteen eyes (90.5%) had stable or improved vision at 6 months of follow-up. One month after conbercept injection, in OCTA images, the small-diameter blood vessels of the MNV decreased, the intertwined small blood vessels decreased or even disappeared, and the main or larger-diameter blood vessels were still present. The mean selected MNV and blood flow areas were 0.62 ± 0.81 and 0.22 ± 0.27 mm2, respectively, before treatment and decreased to 0.23 ± 0.33 and 0.07 ± 0.08 mm2 (P = 0.04 for both), respectively, 1 month after treatment. No drug-related systemic or ocular adverse effects were observed. Our results suggest that conbercept can effectively and safely improve BCVA and reduce CMT in patients with myopic MVN (mMNV). OCTA can be used to observe MNV area, blood flow area, and MNV morphological changes after treatment with conbercept, thus providing a reference for treatment follow-up.

3D Bioprinting-Tunable Small-Diameter Blood Vessels with Biomimetic Biphasic Cell Layers.

Blood vessel damage resulting from trauma or diseases presents a serious risk of morbidity and mortality. Although synthetic vascular grafts have been successfully commercialized for clinical use, they are currently only readily available for large-diameter vessels (>6 mm). Small-diameter vessel (<6 mm) replacements, however, still present significant clinical challenges worldwide. The primary objective of this study is to create novel, tunable, small-diameter blood vessels with biomimetic two distinct cell layers [vascular endothelial cell (VEC) and vascular smooth muscle cell (VSMC)] using an advanced coaxial 3D-bioplotter platform. Specifically, the VSMCs were laden in the vessel wall and VECs grew in the lumen to mimic the natural composition of the blood vessel. First, a novel bioink consisting of VSMCs laden in gelatin methacryloyl (GelMA)/polyethylene(glycol)diacrylate/alginate and lyase was designed. This specific design is favorable for nutrient exchange in an ambient environment and simultaneously improves laden cell proliferation in the matrix pore without the space restriction inherent with substance encapsulation. In the vessel wall, the laden VSMCs steadily grew as the alginate was gradually degraded by lyase leaving more space for cell proliferation in matrices. Through computational fluid dynamics simulation, the vessel demonstrated significantly perfusable and mechanical properties under various flow velocities, flow viscosities, and temperature conditions. Moreover, both VSMCs in the scaffold matrix and VECs in the lumen steadily proliferated over time creating a significant two-cell-layered structure. Cell proliferation was confirmed visually through staining the markers of alpha-smooth muscle actin and cluster of differentiation 31, commonly tied to angiogenesis phenomena, in the vessel matrices and lumen, respectively. Furthermore, the results were confirmed quantitatively through gene analysis which suggested good angiogenesis expression in the blood vessels. This study demonstrated that the printed blood vessels with two distinct cell layers of VECs and VSMCs could be potential candidates for clinical small-diameter blood vessel replacement applications.

Electronic Blood Vessel

Summary Advances in bioelectronics have great potential to address unsolved biomedical problems in the cardiovascular system. By using poly(L-lactide-co-ϵ-caprolactone), which encapsulates liquid metal to make flexible and biodegradable electrical circuitry, we develop an electronic blood vessel that can integrate flexible electronics with three layers of blood-vessel cells, to mimic and go beyond the natural blood vessel. It can improve the endothelialization process through electrical stimulation and can enable controlled gene delivery into specific parts of the blood vessel via electroporation. The electronic blood vessel has excellent biocompatibility in the vascular system and shows great patency 3 months post-implantation in a rabbit model. The electronic blood vessel would be an ideal platform to enable diagnostics and treatments in the cardiovascular system and can greatly empower personalized medicine by creating a direct link of the vascular tissue-machine interface.

Bioprinting of Small-Diameter Blood Vessels

There has been an increasing demand for bioengineered blood vessels for utilization in both regenerative medicine and drug screening. However, the availability of a true bioengineered vascular graft remains limited. Three-dimensional (3D) bioprinting presents a potential approach for fabricating blood vessels or vascularized tissue constructs of various architectures and sizes for transplantation and regeneration. In this review, we summarize the basic biology of different blood vessels, as well as 3D bioprinting approaches and bioink designs that have been applied to fabricate vascular and vascularized tissue constructs, with a focus on small-diameter blood vessels.

Syntheses and characterization of anti-thrombotic and anti-oxidative Gastrodin-modified polyurethane for vascular tissue engineering

Vascular grafts must avoid negative inflammatory responses and thrombogenesis to prohibit fibrotic deposition immediately upon implantation and promote the regeneration of small diameter blood vessels (<6 mm inner diameter). Here, polyurethane (PU) elastomers incorporating anti-coagulative and anti-inflammatory Gastrodin were fabricated. The films had inter-connected pores with porosities equal to or greater than 86% and pore sizes ranging from 250 to 400 μm. Incorporation of Gastrodin into PU films resulted in desirable mechanical properties, hydrophilicity, swelling ratios and degradation rates without collapse. The released Gastrodin maintained bioactivity over 21 days as assessed by its anti-oxidative capability. The Gastrodin/PU had better anti-coagulation response (less observable BSA, fibrinogen and platelet adhesion/activation and suppressed clotting in whole blood). Red blood cell compatibility, measured by hemolysis, was greatly improved with 2Gastrodin/PU compared to other Gastrodin/PU groups. Notably, Gastrodin/PU upregulated anti-oxidant factors Nrf2 and HO-1 expression in H2O2 treated HUVECs, correlated with decreasing pro-inflammatory cytokines TNF-α and IL-1β in RAW 264.7 cells. Upon implantation in a subcutaneous pocket, PU was encapsulated by an obvious fibrous capsule, concurrent with a large amount of inflammatory cell infiltration, while Gastrodin/PU induced a thinner fibrous capsule, especially 2Gastrodin/PU. Further, enhanced adhesion and proliferation of HUVECs seeded onto films in vitro demonstrated that 2Gastrodin/PU could help cell recruitment, as evidenced by rapid host cell infiltration and substantial blood vessel formation in vivo. These results indicate that 2Gastrodin/PU has the potential to facilitate blood vessel regeneration, thus providing new insight into the development of clinically effective vascular grafts.

Biologically Functionalized Expanded Polytetrafluoroethylene Blood Vessel Grafts.

Cardiovascular diseases plague human health because of the lack of transplantable small-diameter blood vessel (SDBV) grafts. Although expanded polytetrafluoroethylene (ePTFE) has the potential to be used as a biocompatible material for SDBV grafts, long-term patency is still the biggest challenge. As discussed in this paper, by virtue of a novel material formulation and a new and benign alcohol/water lubricating agent, biofunctionalized ePTFE blood vessel grafts aimed at providing long-term patency were fabricated. Compared to the most prevalent modification of PTFE, namely surface treatment, this method realized bulk treatment, which could guarantee homogeneous and long-lasting performance throughout PTFE products. These blood vessel grafts included embedded functional biomolecules, such as arginylglycylaspartic acid, heparin, and selenocystamine, using water as a solvent in paste extrusion and in the expansion of ePTFE. Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscope results confirmed the existence of these targeting biomolecules in the as-fabricated ePTFE blood vessel grafts. Meanwhile, the greatly improved biological functions of the grafts were demonstrated via live and dead assays, cell morphology, CD31 staining, nitric oxide (NO) release, and anticoagulation tests. This novel and benign material formulation and fabrication method provides an opportunity to produce multibiofunctional ePTFE blood vessel grafts in a single step, thus yielding a potent product with significant commercial and clinical potential.

Bioprinting small diameter blood vessel constructs with an endothelial and smooth muscle cell bilayer in a single step

Bioengineered artificial blood vessels have been a major area of interest over the last decade. Of particular interest are small diameter vessels, as surgical options are currently limited. This study aimed to fabricate a small diameter, heterogeneous bilayer blood vessel-like construct in a single step with gelatin methacryloyl (GelMA) bioink using a 3D micro-extrusion bioprinter on a solid platform. GelMA was supplemented with Hyaluronic acid (HA), glycerol and gelatin to form a GelMA bioink with good printability, mechanical strength, and biocompatibility. Two separate concentrations of GelMA bioink with unique pore sizes were selected to fabricate a heterogeneous bilayer. A higher concentration of GelMA bioink (6% w/v GelMA, 2% gelatin, 0.3% w/v HA, 10% v/v glycerol) was used to load human umbilical vein endothelial cells (HUVECs) and form an inner, endothelial tissue layer. A lower concentration of GelMA bioink (4% w/v GelMA, 4% gelatin, 0.3% w/v HA, 10% v/v glycerol) was used to load smooth muscle cells (SMCs) and form an outer, muscular tissue layer. Bioprinted blood vessel-like grafts were then assessed for mechanical properties with Instron mechanical testing, and suture-ability, and for biological properties including viability, proliferation, and histological analysis. The resulting 20 mm long, 4.0 mm diameter lumen heterogeneous bilayer blood vessel-like construct closely mimics a native blood vessel and maintains high cell viability and proliferation. Our results represent a novel strategy for small diameter blood vessel biofabrication.

Structure and Thermomechanical Properties of Tubes Based on Poly(L-lactide) Microfibers

Using X-ray diffraction, electron microscopy, and differential scanning calorimetry, the structure and mechanical properties of tubes based on poly (L-lactide) microfibers obtained by electrospinning from a dichloroethane solution and designed for implantation in small diameter blood vessels during prosthetics are studied. It is shown that freshly formed microfibers have an amorphous structure and their heat treatment at a temperature of 70–160°С is accompanied by crystallization of the polymer. Microfibers consist of lamellas ~20 × 200 nm in size, and their crystallites, the sizes of which depend on the processing temperature and amount to 25–34 nm, are characterized by the α-modification. The mechanical characteristics of the obtained tubes are considered.

Expanded Poly(tetrafluoroethylene) Blood Vessel Grafts with Embedded Reactive Oxygen Species (ROS)-Responsive Antithrombogenic Drug for Elimination of Thrombosis.

Treatment of cardiovascular diseases suffers from the lack of transplantable small-diameter blood vessel (SDBV) grafts that can prohibit/eliminate thrombosis. Although expanded poly(tetrafluoroethylene) (ePTFE) has the potential to be used for SDBV grafts, recurrence of thrombus remains the biggest challenge. In this study, a reactive oxygen species (ROS)-responsive antithrombogenic drug synthesis and a bulk coating process were employed to fabricate functional ePTFE grafts capable of prohibiting/eliminating blood clots. The synthesized drug that would release antiplatelet ethyl salicylate (ESA), in responding to ROS, was dissolved in a polycaprolactone (PCL) solution, followed by a bulk coating of the as-fabricated ePTFE grafts with the PCL/drug solution. Nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM) were employed to investigate and confirm the synthesis and presence of the ROS-responsive drug in the ePTFE grafts. The ESA release functions were demonstrated via the drug-release profile and dynamic anticoagulation tests. The biocompatibility of the ROS-responsive ePTFE grafts was demonstrated via lactate dehydrogenase (LDH) cytotoxicity assays, live and dead cell assays, cell morphology, and cell-graft interactions. The ROS-responsive, antithrombogenic ePTFE grafts provide a feasible way for maintaining long-term patency, potentially solving a critical challenge in SDBV applications.

806 Bioprinted skin integrates and forms epidermal rete ridges in full-thickness wounds

Current tissue engineered skin fails to meet the need for skin replacement in full-thickness wounds. Bioprinting technology allows for fabrication of full-thickness skin with multiple cell types organized into biomimetic layers in vitro. The purpose of this study is to determine if bioprinted skin will integrate, form an epidermal barrier, and vascularize when implanted into full-thickness wounds on mice. Cells were isolated from human skin, expanded in vitro, suspended in a fibrinogen bioink, bioprinted to form a biomimetic tri-layer skin construct, and implanted onto 2.5 x 2.5cm full-thickness excisional wounds on mice. A significant difference in total wound closure was found between bioprinted skin and non-treated wounds, as well as an accelerated time to wound closure (14.8 vs. 24.5 days, p<0.001). By day 90, H&E and Masson’s trichrome staining revealed rete ridge formation in the bioprinted skin comparable to native human epidermis, compared with a flat epidermis in controls. Picrosirius red stained samples demonstrated a normal basket weave collagen orientation in bioprinted skin-treated wounds, and hypertrophic scar-like, parallel collagen alignment in controls (41.3% vs. 80.0% alignment, p<0.001). Immunohistochemical staining confirmed the presence of human cells in the regenerated skin, the formation of epidermal rete ridges, and incorporation of human endothelial cells in infiltrating host blood vessels. Measurement of blood vessels demonstrated an increase in small diameter blood vessels in bioprinted skin treated wounds compared to control (8.4 vs. 4.3 blood vessels, p<0.01). In conclusion, bioprinted skin accelerates full-thickness wound closure, with implanted cells laying down a healthy, basket-weave collagen matrix. The remodeled skin forms epidermal rete ridges and a vascular network composed of both graft and infiltrating host vessels. Ultimately, this technology could translate into a new treatment for full-thickness wounds in human patients.

Characterization of a heparinized decellularized scaffold and its effects on mechanical and structural properties

Decellularization is a promising approach in tissue engineering to generate small-diameter blood vessels. However, some challenges still exist. We performed two decellularization phases to develop an optimal decellularized scaffold and analyze the relationship between the extracellular matrix (ECM) composition and mechanical properties. In decellularization phase I, we tested sodium dodecylsulfate (SDS), Triton X-100 (TX100) and trypsin at different concentrations and exposure times. In decellularization phase II, we systematically compared five combined decellularization protocols based on the results of phase I to identify the optimal method. These protocols tested cell removal, ECM preservation, mechanical properties, and residual cytotoxicity. We further immobilized heparin to optimal decellularized scaffolds and determined its anticoagulant activity and mechanical properties. The combined decellularization protocol comprising treatment with 0.5% SDS followed by 1% TX100 could completely remove the cellular contents and preserve the mechanical properties and ECM architecture better. In addition, the heparinized decellularized scaffolds not only had sustained anticoagulant activity, but also similar mechanical properties to native vessels. In conclusion, heparinized decellularized scaffolds represent a promising direction for small-diameter vascular grafts, although further in vivo studies are needed.

Polyurethane/polycaprolactone membrane grafted with conjugated linoleic acid for artificial vascular graft application

ABSTRACT Constructing satisfied small-diameter vascular graft (diameter less than 6 mm) remains an unsolvable challenge in vascular tissue engineering. This study described the fabrication of electrospun polyurethane/polycaprolactone (PU/PCL) membranes chemically grafted with various densities of conjugated linoleic acid (CLA) – an antithrombotic fatty acid – for making small-diameter blood vessel. Differences in mechanical, antithrombotic properties and biocompatibility of the membranes resulting from the CLA-grafting procedure were the focus of the study. Investigation of mechanical properties relevant to vascular graft application revealed that these properties of the membranes remained unaffected and satisfied clinical criteria following the CLA graft. Blood–membrane interaction assays showed that the CLA-grafted membranes mitigated the adhesion of blood cells, as well as preventing blood coagulation. These effects were also commensurate with increasing density of CLA, suggesting an effective approach to improve antithromboticity. Cellular tests suggested that CLA has an optimal density at which it promoted cell proliferation on the surface of the membranes; however, excessive presence of CLA might cause undesirable inhibition on cells. In conclusion, PU/PCL membrane grafted with CLA could be a prospective material for vascular tissue engineering with further development and investigation.

Small diameter blood vessels with controllable micropore structure induced by centrifugal force for improved endothelialization.

The micropore structure is prerequisite for fast and durable endothelialization of artificial small diameter blood vessels (ASDBVs). Although some methods, such as salt leaching, coagulation, and electrospinning, have been developed to construct micropores for ASDBVs, the uncontrollability of the structure and the complicated procedures of the process are still the issues to be concerned about. In this study, a compact device based on the principle of centrifugal force is established and used to prepare polyurethane (PU) ASDBVs with micropore structures by blasting different porogens. It is found that the glass beads could construct micropores with regular round shape, uniform distribution, and controllable size (60–350 µm), which significantly improves the endothelialization of PU‐based ASDBVs, especially when the pore size is about 60 µm. This method is easy‐accessible and wide‐applicable, which provides a new pathway for the research and development of ASDBVs.

Electrostatic Self-Assemble Modified Electrospun Poly-L-Lactic Acid/Poly-Vinylpyrrolidone Composite Polymer and Its Potential Applications in Small-Diameter Artificial Blood Vessels.

Large (> 6 mm) artificial blood vessels have been successfully employed in clinic practice. However, small-diameter (< 6 mm) synthetic grafts have not been applied due to their hydrophobicity. In this study, poly-vinylpyrrolidone (PVP) was introduced into poly-L-lactic acid (PLLA) to prepare biodegradable small-diameter electrospun blood vessels which were further modified via electrostatic self-assembly (ESA). The characteristics of PLLA/PVP films were investigated by scanning electron microscopy (SEM), contact angle measurement and mechanical property testing. The cytocompatiblility and blood compatibility of the fiber films were further studied through vascular smooth muscle cells (VSMCs) proliferation and platelet adhesion, and the morphology of cells on films was viewed by laser scanning confocal microscopy (LSCM) and SEM. Next, the surface of ESA-modified electrospun fiber films was analyzed through SEM and photoelectron spectroscopy (XPS). The degradation characteristics of these films were investigated through SEM observation, weight loss, viscosity average molecular weight reduction, and pH change in the testing solutions as well. The films were also subcutaneously implanted in rabbits to analyze the biocompatibility. The results of these experiments showed that electrospun films with PVP possessed a good structure and improved hydrophilicity. The films assembled with chitosan/heparin by ESA were beneficial to VSMCs survival and had excellent blood compatibilities. The data indicated these films were biodegradable with good tissue compatibility. In conclusion, we successfully obtained biodegradable small-diameter blood vessels through electrospinning PLLA/PVP and modifying this blend's surface using ESA. The study provided a feasible method for making small-diameter synthetic blood vessels with improved hydrophilic and anticoagulant properties.

Fabrication of PCL/keratin composite scaffolds for vascular tissue engineering with catalytic generation of nitric oxide potential.

Tissue-engineered vascular grafts (TEVGs) have been proposed as a promising approach to fulfill the need for small-diameter blood vessel substitutes. However, common failure caused by thrombosis and neointimal proliferation after implantation has restricted their use in the clinic. Herein, a NO-generating scaffold for vascular tissue engineering was developed by coelectrospinning poly(ε-caprolactone) (PCL) with keratin. The morphology and surface chemical composition were characterized via SEM, ATR-FTIR spectroscopy and XPS. The biocomposite scaffold selectively enhanced the adhesion and growth of endothelial cells (ECs) while suppressing the proliferation of smooth muscle cells (SMCs) in the presence of GSH and GSNO due to the catalytic generation of NO. In addition, these mats displayed excellent blood compatibility by prolonging the blood-clotting time. In summary, these NO-generating PCL/keratin scaffolds have potential applications in vascular tissue engineering with rapid endothelialization and reduced SMC proliferation.

Artificial small-diameter blood vessels: materials, fabrication, surface modification, mechanical properties, and bioactive functionalities

Cardiovascular diseases, especially ones involving narrowed or blocked blood vessels with diameters smaller than 6 millimeters, are the leading cause of death globally. Vascular grafts have been used in bypass surgery to replace damaged native blood vessels for treating severe cardio- and peripheral vascular diseases. However, autologous replacement grafts are not often available due to prior harvesting or the patient's health. Furthermore, autologous harvesting causes secondary injury to the patient at the harvest site. Therefore, artificial blood vessels have been widely investigated in the last several decades. In this review, the progress and potential outlook of small-diameter blood vessels (SDBVs) engineered in vitro are highlighted and summarized, including material selection and development, fabrication techniques, surface modification, mechanical properties, and bioactive functionalities. Several kinds of natural and synthetic polymers for artificial SDBVs are presented here. Commonly used fabrication techniques, such as extrusion and expansion, electrospinning, thermally induced phase separation (TIPS), braiding, 3D printing, hydrogel tubing, gas foaming, and a combination of these methods, are analyzed and compared. Different surface modification methods, such as physical immobilization, surface adsorption, plasma treatment, and chemical immobilization, are investigated and are compared here as well. Mechanical requirements of SDBVs are also reviewed for long-term service. In vitro biological functions of artificial blood vessels, including oxygen consumption, nitric oxide (NO) production, shear stress response, leukocyte adhesion, and anticoagulation, are also discussed. Finally, we draw conclusions regarding current challenges and attempts to identify future directions for the optimal combination of materials, fabrication methods, surface modifications, and biofunctionalities. We hope that this review can assist with the design, fabrication, and application of SDBVs engineered in vitro and promote future advancements in this emerging research field.