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The present study has attempted to evaluate the endothelialization and smooth muscle regeneration efficiency of a novel dual‐layer small‐diameter vascular graft. Two types of layers (PCL‐mPEG‐VEGF and PCL‐Chitosan‐PDGF) were fabricated to find out the best layer giving endothelialization support for the lumen and unique contractile function for outer layer of blood vessels. Platelet‐derived growth factor (PDGF) and chitosan were immobilized onto PCL surface by aminolysis‐based surface modification technique. Besides, Poly (ethylene glycol) methyl ether (mPEG) and vascular endothelial growth factor (VEGF) were directly blended with PCL. Morphological analysis of membranes ensured consistency of average fibers diameter with native extracellular matrix. A favorable interaction of PCL‐mPEG‐VEGF with cow pulmonary endothelial cells (CPAEs) and PCL‐Chitosan‐PDGF with rat bone marrow mesenchymal stem cells (RBMSCs) was obtained during in vitro study. Controlled growth factor release patterns were found from both layers. Further, PCL‐mPEG‐VEGF exhibited endothelial markers expression properties from RBMSCs. Up‐regulation of SMCs markers expression was significantly ensured by the PCL‐Chitosan‐PDGF membrane. Thus, PCL‐mPEG‐VEGF and PCL‐Chitosan‐PDGF were preferred as inner and outer layers respectively of a finally prepared tubular hybrid tissue engineered small diameter vascular graft. Finally, the dual‐layer vascular graft was implanted onto a rat abdominal aorta model for 2 months. The extracted samples exhibited the presence of endothelial marker (ICAM 1) in the inner layer and smooth muscle cell marker (αSMA) in the outer layer as well as substantial amount of collagen deposition was observed in the both layers. [ABSTRACT FROM AUTHOR]

Thrombogenesis remains the primary failure of synthetic vascular grafts. Endothelial coverage is crucial to provide an antithrombogenic surface. However, most synthetic materials do not support cell adhesion, and transanastomotic endothelial migration is limited. Here, a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol, which is not endothelial cell-adhesive. Among three different immobilization approaches compared, conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay. Screening of six topographical patterns showed that 2 μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells. Mechanistic studies demonstrated that fucoidan could attract fibronectin, enabling integrin binding and focal adhesion formation and activating focal adhesion kinase (FAK) signaling, and 2 μm gratings further enhanced FAK-mediated cell migration. In a clinically relevant rabbit carotid artery end-to-side anastomosis model, 60% in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts, compared to 0% of unmodified graft, and the four-week graft patency also increased. This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.

There are no small‐diameter, long artificial vascular grafts for below‐knee bypass surgery in chronic limb‐threatening ischemia. We have developed tissue‐engineered vascular grafts called "Biotubes®" using a completely autologous approach called in‐body tissue architecture (iBTA). This study aimed at pre‐implantation evaluation of Biotube and its in vivo preparation device, Biotube Maker, for use in below‐knee bypass surgery. Forty nine makers were subcutaneously embedded into 17 goats for predetermined periods (1, 2, or 3 months). All makers produced Biotubes as designed without inflammation over all periods, with the exception of a few cases with minor defects (success rate: 94%). Small hole formation occurred in only a few cases. All Biotubes obtained had an inner diameter of 4 mm and a length of 51 to 52 cm with a wall thickness of 594 ± 97 μm. All Biotubes did not kink when completely bent under an internal pressure of 100 mmHg and did not leak without any deformation under a water pressure of 200 mmHg. Their burst strength was 2409 ± 473 mmHg, and suture retention strength was 1.75 ± 0.27 N, regardless of the embedding period, whereas tensile strength increased from 7.5 ± 1.3 N at 1 month to 9.7 ± 2.0 N at 3 months with the embedding period. The amount of water leakage from the needle holes prepared in the Biotube wall was approximately 1/7th of that in expanded polytetrafluoroethylene vascular grafts. The Biotubes could be easily connected to each other without cutting or anastomosis leaks. They could be stored for at least 1 year at room temperature. This study confirmed that even Biotubes formed 1 month after embedding of Biotube Makers had properties comparable to arteries. [ABSTRACT FROM AUTHOR]

Abstract Background Nowadays, the engineering vascular grafts with a diameter less than 6 mm by means of electrospinning, is an attracted alternative technique to create different three-dimensional microenvironments with appropriate physicochemical properties to promote the nutrient transport and to enable the bioactivity, dynamic growth and differentiation of cells. Although the performance of a well-designed porous wall is key for these functional requirements maintaining the mechanical function, yet predicting the flow rate and cellular transport are still not widely understood and many questions remain open about new configurations of wall can be used for modifying the conventional electrospun samples. The aim of the present study was to evaluate the effect of fabrication techniques on scaffolds composed of bovine gelatin and polycaprolactone (PCL) developed by sequential electrospinning and co-electrospinning, on the morphology and fluid-mechanical properties of the porous wall. Methodology For this purpose, small diameter tubular structures were manufactured and experimental tests were performed to characterize the crystallinity, morphology, wettability, permeability, degradability, and mechanical properties. Some samples were cross-linked with Glutaraldehyde (GA) to improve the stability of the gelatin fiber. In addition, it was analyzed how the characteristics of the scaffold favored the levels of cell adhesion and proliferation in an in vitro model of 3T3 fibroblasts in incubation periods of 24, 48 and 72 h. Results It was found that in terms of the morphology of tubular scaffolds, the co-electrospun samples had a better alignment with higher values of fiber diameters and apparent pore area than the sequential samples. The static permeability was more significant in the sequential scaffolds and the hydrophilic was higher in the co-electrospun samples. Therefore, the gelatin mass losses were less in the co-electrospun samples, which promote cellular functions. In terms of mechanical properties, no significant differences were observed for different types of samples. Conclusion This research concluded that the tubular scaffolds generated by sequential and co-electrospinning with modification in the microarchitecture could be used as a vascular graft, as they have better permeability and wettability, interconnected pores, and a circumferential tensile strength similar to native vessel compared to the commercial graft analyzed.

The main objective of the present review article is to investigate the in-vitro and in-vivo biocompatibility behavior of hybrid PCL-based scaffolds with collagen, gelatin, and chitosan to improve endothelialization for VTE applications. It is reported that the high-rate failure of small diameters vascular grafts (SDVGs, <6 mm) due to adhesion of platelets and plasma protein and aggregation, over-proliferation of smooth muscle cells (SMCs), and neointimal hyperplasia at the implantation site is main challenge in vascular tissue engineering (VTE). The fast re-establishment of a functional endothelial cell (EC) layer representing a crucial importance strategy has been proposed to reduce these adverse outcomes. Polycaprolactone (PCL), with optimum mechanical properties, it showed great potential in biomedical applications, but its biocompatibility is still highly concerned in VTE. Modifications of the PCL vascular grafts by developing the hybrid structures using natural polymers with optimum hydrophilicity and biocompatibility properties in order to speed up the re-endothelialization process have been proposed over the last years. Analyzing the mentioned results in the present study can offer a better understanding of the benefits and challenges of applying the natural polymer as a thrombotic response upon implantation in clinical trials. Also, it can suggest the PCL-Collagen as the best framework for the fabrication of rationally designed SDVGs for VTE. [ABSTRACT FROM AUTHOR]

Objective: In the past five decades, many small caliber vascular grafts have been developed as bypasses for infrapopliteal or coronary arteries. However, reliable grafts have not been obtained owing to poor patency, mainly caused by early thrombosis or neointimal hyperplasia in the intermediate period after implantation. We developed a novel small caliber heparin-loaded polyethylene terephthalate ultrafine microfiber (HL-PET) graft and evaluated the feasibility to overcome those main causes of graft failure in canine carotid artery implantation. Methods: The HL-PET graft with a diameter of 3 mm and length of 30 mm was made with combination of three key technologies: (1) weaving with PET ultrafine microfiber with a high biological porosity allowing for cell ingrowth, (2) heparin loading on microfiber surfaces, and (3) an outer coating with a flexible bioabsorbable polymer for prevention of blood leakage and graft kinking. Kink resistance, water permeability, and loaded heparin were assessed. One HL-PET graft each was implanted into a carotid artery of six animals. Graft patency rate and healing were assessed 24 weeks after implantation. Results: Among the six grafts, five were deemed patent (patency rate of >83%), with one occluded 20 weeks after implantation. Histopathology of the patent grafts showed neointima formation with confluent endothelial cell lining (estimated mean endothelial cell coverage area, 89 ± 18%). Intimal hyperplasia at the anastomotic sites and severe chronic inflammatory responses were not observed. Immunohistochemistry with antibodies to endothelial nitric oxide synthase, alpha 2 smooth muscle actin and calponin 1 revealed luminal surface endothelial cell layer with expression of endothelial nitric oxide synthase and vascular smooth muscle cells with contractile phenotype in the subintimal layer. Conclusions: The HL-PET graft showed no early postoperative thrombosis and was able to demonstrate a high patency rate with no severe biological response observed after 24 weeks. These results strongly suggest the potential of the HL-PET graft to be used for distal bypasses. : Clinical Relevance: The HL-PET graft achieved a high patency rate without early postoperative thrombosis or intimal hyperplasia in a small caliber artery implantation study. The histopathologic analysis demonstrated favorable healing property with a high antithrombogenicity. These results strongly suggested the possible use of the HL-PET graft as a bypass for infrapopliteal or coronary arteries.

All human tissues present with unique mechanical properties critical to their function. This is achieved in part through the specific architecture of the extracellular matrix (ECM) fibres within each tissue. An example of this is seen in the walls of the vasculature where each layer presents with a unique ECM orientation critical to its functions. Current adopted vascular grafts to bypass a stenosed/damaged vessel fail to recapitulate this unique mechanical behaviour, particularly in the case of small diameter vessels (<6 mm), leading to failure. Therefore, in this study, melt-electrowriting (MEW) was adopted to produce a range of fibrous scaffolds to mimic the extracellular matrix (ECM) architecture of the tunica media of the vasculature, in an attempt to match the mechanical and biological behaviour of the native porcine tissue. Initially, the range of collagen architectures within the native vessel was determined, and subsequently replicated using MEW (winding angles (WA) 45°, 26.5°, 18.4°, 11.3°). These scaffolds recapitulated the anisotropic, non-linear mechanical behaviour of native carotid blood vessels. Moreover, these grafts facilitated human mesenchymal stem cell (hMSC) infiltration, differentiation, and ECM deposition that was independent of WA. The bioinspired MEW fibre architecture promoted cell alignment and preferential neo-tissue orientation in a manner similar to that seen in native tissue, particularly for WA 18.4° and 11.3°, which is a mandatory requirement for long-term survival of the regenerated tissue post-scaffold degradation. Lastly, the WA 18.4° was translated to a tubular graft and was shown to mirror the mechanical behaviour of small diameter vessels within physiological strain. Taken together, this study demonstrates the capacity to use MEW to fabricate bioinspired scaffolds to mimic the tunica media of vessels and recapitulate vascular mechanics which could act as a framework for small diameter graft development to guide tissue regeneration and orientation. [ABSTRACT FROM AUTHOR]

Vascular grafts with a diameter of less than 6 mm are made from a variety of materials and techniques to provide alternatives to autologous vascular grafts. Decellularized materials have been proposed as a possible approach to create extracellular matrix (ECM) vascular prostheses as they are naturally derived and inherently support various cell functions. However, these desirable graft characteristics may be limited by alterations of the ECM during the decellularization process leading to decreased biomechanical properties and hemocompatibility. In this study, arteries from the human placenta chorion were decellularized using two distinct detergents (Triton X-100 or SDS), which differently affect ECM ultrastructure. To overcome biomechanical strength loss and collagen fiber exposure after decellularization, riboflavin-mediated UV (RUV) crosslinking was used to uniformly crosslink the collagenous ECM of the grafts. Graft characteristics and biocompatibility with and without RUV crosslinking were studied in vitro and in vivo. RUV-crosslinked ECM grafts showed significantly improved mechanical strength and smoothening of the luminal graft surfaces. Cell seeding using human endothelial cells revealed no cytotoxic effects of the RUV treatment. Short-term aortic implants in rats showed cell migration and differentiation of host cells. Functional graft remodeling was evident in all grafts. Thus, RUV crosslinking is a preferable tool to improve graft characteristics of decellularized matrix conduits. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Background: Current design strategies for small diameter vascular grafts (< 6 mm internal diameter; ID) are focused on mimicking native vascular tissue because the commercially available grafts still fail at small diameters, notably due to development of intimal hyperplasia and thrombosis. To overcome these challenges, various design approaches, material selection, and surface modification strategies have been employed to improve the patency of small-diameter grafts. Review: The purpose of this review is to outline various considerations in the development of small-diameter vascular grafts, including material choice, surface modifications to enhance biocompatibility/endothelialization, and mechanical properties of the graft, that are currently being implanted. Additionally, we have taken into account the general vascular physiology, tissue engineering approaches, and collective achievements of the authors in this area. We reviewed both commercially available synthetic grafts (e-PTFE and PET), elastic polymers such as polyurethane and biodegradable and bioresorbable materials. We included naturally occurring materials by focusing on their potential application in the development of future vascular alternatives. Conclusion: Until now, there are few comprehensive reviews regarding considerations in the design of small-diameter vascular grafts in the literature. Here-in, we have discussed in-depth the various strategies employed to generate engineered vascular graft due to their high demand for vascular surgeries. While some TEVG design strategies have shown greater potential in contrast to autologous or synthetic ePTFE conduits, many are still hindered by high production cost which prevents their widespread adoption. Nonetheless, as tissue engineers continue to develop on their strategies and procedures for improved TEVGs, soon, a reliable engineered graft will be available in the market. Hence, we anticipate a viable TEVG with resorbable property, fabricated via electrospinning approach to hold a greater potential that can overcome the challenges observed in both autologous and allogenic grafts. This is because they can be mechanically tuned, incorporated/surface-functionalized with bioactive molecules and mass-manufactured in a reproducible manner. It is also found that most of the success in engineered vascular graft approaching commercialization is for large vessels rather than small-diameter grafts used as cardiovascular bypass grafts. Consequently, the field of vascular engineering is still available for future innovators that can take up the challenge to create a functional arterial substitute. [ABSTRACT FROM AUTHOR]

Biodegradable materials for in situ vascular tissue engineering could meet the increasing clinical demand for sufficient synthetic small diameter vascular substitutes in aortocoronary bypass and peripheral vascular surgery. The aim of this study was to design a new degradable thermoplastic polycarbonate urethane (dPCU) with improved biocompatibility and optimal biomechanical properties. Electrospun conduits made from dPCU were evaluated in short and long term follow up and compared with expanded polytetrafluoroethylene (ePTFE) controls. Both conduits were investigated prior to implantation to assess their biocompatibility and inflammatory potential via real time polymerase chain reaction using a macrophage culture. dPCU grafts (n = 28) and ePTFE controls (n = 28) were then implanted into the infrarenal abdominal aorta of Sprague–Dawley rats. After seven days, one, six, and 12 months, grafts were analysed by histology and immunohistochemistry (IHC) and assessed biomechanically. Anti-inflammatory signalling was upregulated in dPCU conduits and increased significantly over time in vitro. dPCU and ePTFE grafts offered excellent long and short term patency rates (92.9% in both groups at 12 months) in the rat model without dilatation or aneurysm formation. In comparison to ePTFE, dPCU grafts showed transmural ingrowth of vascular specific cells resulting in a structured neovessel formation around the graft. The graft material was slowly reduced, while the compliance of the neovessel increased over time. The newly designed dPCU grafts have the potential to be safely applied for in situ vascular tissue engineering applications. The degradable substitutes showed good in vivo performance and revealed desirable characteristics such as biomechanical stability, non-thrombogenicity, and minimal inflammatory response after long term implantation. [ABSTRACT FROM AUTHOR]

In this paper, we investigate essential mechanical properties and cell behaviors of the scaffolds fabricated by rolling polylactic-co-glycolic acid (PLGA) electrospinning (ES) films for small-diameter vascular grafts (inner diameter < 6 mm). The newly developed strategy can be used to fabricate small diameter vascular grafts with or without pre-seeded cells, which are two main branches for small diameter vascular engineering. We demonstrate that the mechanical properties of our rolling-based scaffolds can be tuned flexibly by the number of layers. For cell-free scaffolds, with the increase of layer number, burst pressure and suture retention increase, elastic tensile modulus maintains unchanged statistically, but compliance and liquid leakage decrease. For cell-containing scaffolds, seeding cells will significantly decrease the liquid leakage, but there are no statistical differences for other mechanical properties; moreover, cells live and proliferate well in the scaffold after a 6-day culture. [ABSTRACT FROM AUTHOR]

The lack of a blood compatible synthetic interface is one of the largest unaddressed challenges in the field of biomaterials science. This technological shortcoming hinders the successful clinical application of small diameter vascular grafts and other cardiovascular devices such as stents and artificial heart valves. Therefore, intensive research activities are ongoing to develop polymer materials with improved blood compatibility. One attractive strategy to improve the blood compatibility of an interface is to design surfaces that promote the development of an endothelium, the monolayer of endothelial cells that line our native vasculature and is responsible for blood compatibility. This article describes the recent strategies that have been used to generate polymeric materials that promote the development of an endothelium, discusses shortcomings in the field, and proposes future directions of research that can be undertaken to design next generation polymeric biomaterial that promote endothelialization. [ABSTRACT FROM AUTHOR]

Coronary heart disease is a leading cause of death among Americans for which coronary artery bypass graft (CABG) surgery is a standard surgical treatment. The success of CABG surgery is impaired by a compliance mismatch between vascular grafts and native vessels. Tissue engineered vascular grafts (TEVGs) have the potential to be compliance matched and thereby reduce the risk of graft failure. Glutaraldehyde (GLUT) vapor-crosslinked gelatin/fibrinogen constructs were fabricated and mechanically tested in a previous study by our research group at 2. 8, and 24 hrs of GLUT vapor exposure. The current study details a computational method that was developed to predict the material properties of our constructs for crosslinking times between 2 and 24 hrs by interpolating the 2. 8, and 24 hrs crosslinking time data. MATLAB and ABAQUS were used to determine the optimal combination of fabrication parameters to produce a compliance matched construct. The validity of the method was tested by creating a 16-hr crosslinked construct of 130 pm thickness and comparing its compliance to that predicted by the optimization algorithm. The predicted compliance of the 16-hr construct was 0.00059 mm Hg-1 while the experimentally determined compliance was 0.00065 mm Hg-1, a relative difference of 9.2%. Prior data in our laboratory has shown the compliance of the left anterior descending porcine coronary (LADC) artery to he 0.00071 ± 0.0003 mm Hg-1. Our optimization algorithm predicts that a 258-pm-thick construct that is GLUT vapor crosslinked for 8.1 hrs would match LADC compliance. This result is consistent with our previous work demonstrating that an 8-hr GLUT vapor crosslinked construct produces a compliance that is not significantly different from a porcine coronary LADC. [ABSTRACT FROM AUTHOR]

Organ engineering using decellularized scaffolds is a potential long-term solution to donor organ shortage. However, this technology is severely limited by small vessel thrombosis due to incompletely recellularized vessels, resulting in exposure of extracellular matrix (ECM) components to platelets and clotting factors in flowing blood. To address this limitation, we designed a polymer–ECM composite and demonstrated its potential to reduce thrombosis and facilitate re-endothelialization in a vascular graft model. Rat aortas were decellularized using a sequential combination of weak detergents followed by a nuclease treatment that resulted in 96.5 ± 1.3% DNA removal, while ECM components and mechanical properties were well maintained. A biodegradable and biocompatible elastomer poly(1,8 octanediol citrate) (POC, 1 wt.%) was infused throughout the ECM at mild conditions (37 °C and 45 °C) and was functionalized with heparin using carbodiimide chemistry. The polymer–ECM composite significantly reduced platelet adhesion (67.4 ± 8.2% and 82.7 ± 9.6% reduction relative to untreated ECM using one of two processing temperatures, 37 °C or 45 °C, respectively); inhibited whole blood clotting (85.9 ± 4.3% and 87.0 ± 11.9% reduction relative to untreated ECM at 37 °C or 45 °C processing temperature, respectively); and supported endothelial cell—and to a lesser extent smooth muscle cell—adhesion in vitro . Taken together, this novel POC composite may provide a solution for thrombosis of small vessel conduits commonly seen in decellularized scaffolds used in tissue engineering applications. [ABSTRACT FROM AUTHOR]

Acellular biodegradable small diameter vascular grafts (SDVGs) require antithrombosis, intimal hyperplasia inhibition and rapid endothelialization to improve the graft patency. However, current antithrombosis and antiproliferation approaches often conflict with endothelial cell layer formation on SDVGs. To address this limitation, biodegradable elastic polyurethane urea (BPU) and the drug dipyridamole (DPA) were mixed and then electrospun into a biodegradable fibrous scaffold. The BPU would provide the appropriate mechanical support, while the DPA in the scaffold would offer biofunctions as required above. We found that the resulting scaffolds had tensile strengths and strains comparable with human coronary artery. The DPA in the scaffolds was continuously released up to 91 days in phosphate buffer solution at 37 °C, with a low burst release within the first 3 days. Compared to BPU alone, improved non-thrombogenicity of the DPA-loaded BPU scaffolds was evidenced with extended human blood clotting time, lower TAT complex concentration, lower hemolysis and reduced human platelet deposition. The scaffolds with a higher DPA content (5 and 10%) inhibited proliferation of human aortic smooth muscle cell significantly. Furthermore, the DPA-loaded scaffolds had no adverse effect on human aortic endothelial cell growth, yet it improved their proliferation. The attractive mechanical properties and biofunctions of the DPA-loaded BPU scaffold indicate its potential as an acellular biodegradable SDVG for vascular replacement. [ABSTRACT FROM AUTHOR]

Thrombogenesis remains the primary failure of synthetic vascular grafts. Endothelial coverage is crucial to provide an antithrombogenic surface. However, most synthetic materials do not support cell adhesion, and transanastomotic endothelial migration is limited. Here, a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol, which is not endothelial cell-adhesive. Among three different immobilization approaches compared, conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay. Screening of six topographical patterns showed that 2 μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells. Mechanistic studies demonstrated that fucoidan could attract fibronectin, enabling integrin binding and focal adhesion formation and activating focal adhesion kinase (FAK) signaling, and 2 μm gratings further enhanced FAK-mediated cell migration. In a clinically relevant rabbit carotid artery end-to-side anastomosis model, 60% in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts, compared to 0% of unmodified graft, and the four-week graft patency also increased. This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

In order to investigate the in vitro biocompatibility of a novel polyurethane (PU) membrane modified by incorporation of superfine silk-fibroin powder (SFP), which was prepared for small-diameter vascular grafts, with the cultivation of human umbilical vein endothelial cells (HUVECs), PU and SFP were mixed with the ratios of 9:1, 7:3, 5:5, 3:7 (PU:SFP) to make four composite materials. Unmodified PU and polytetrafluoroethylene (PTFE) were added as control groups. CCK-8 assay was used to evaluate the cytotoxicity of these biomaterials. Data were processed using SPSS, and P < 0.05 was considered to be statistically significant. Adherence and spreading of HUVECs on the surface of specimens was observed using direct contact cultivation. The toxicity ratings of the novel composites were grade 0-1, which is in the acceptable range. In all the experimental groups except control, SFP/PU with ratio of 1:9 had the least cytotoxicity property, and more content of SFP in the composite showed no improvement of the biocompatibility. HUVECs strongly attached to and grew on the surface of the biomaterials, and proliferated rapidly. The proliferation ability increased with increased proportion of SFP; however the cell quantity on the surface of the materials decreased when the proportion of SFP was equal to or larger than that of PU in the composite. It is concluded that this novel material has excellent cellular affinity with no cytotoxicity to HUVECs. Adding SFP gives PU better biocompatibility, while further research on optimum blend ratios is still needed. [ABSTRACT FROM AUTHOR]

To address the clinical need for readily available small diameter vascular grafts, biomimetic tubular scaffolds were developed for rapid in situ blood vessel regeneration. The tubular scaffolds were designed to have an inner layer that is porous, interconnected, and with a nanofibrous architecture, which provided an excellent microenvironment for host cell invasion and proliferation. Through the synthesis of poly(spirolactic-co-lactic acid) (PSLA), a highly functional polymer with a norbornene substituting a methyl group in poly(l -lactic acid) (PLLA), we were able to covalently attach biomolecules onto the polymer backbone via thiol-ene click chemistry to impart desirable functionalities to the tubular scaffolds. Specifically, heparin was conjugated on the scaffolds in order to prevent thrombosis when implanted in situ. By controlling the amount of covalently attached heparin we were able to modulate the physical properties of the tubular scaffold, resulting in tunable wettability and degradation rate while retaining the porous and nanofibrous morphology. The scaffolds were successfully tested as rat abdominal aortic replacements. Patency and viability were confirmed through dynamic ultrasound and histological analysis of the regenerated tissue. The harvested tissue showed excellent vascular cellular infiltration, proliferation, and migration with laminar cellular arrangement. Furthermore, we achieved both complete reendothelialization of the vessel lumen and native-like media extracellular matrix. No signs of aneurysm or hyperplasia were observed after 3 months of vessel replacement. Taken together, we have developed an effective vascular graft able to generate small diameter blood vessels that can function in a rat model. [ABSTRACT FROM AUTHOR]

The performance of clinical synthetic small diameter vascular grafts remains disappointing due to the fast occlusion caused by thrombosis and intimal hyperplasia formation. Poly(vinyl alcohol) (PVA) hydrogels have tunable mechanical properties and a low thrombogenic surface, which suggests its potential value as a small diameter vascular graft material. However, PVA does not support cell adhesion and thus requires surface modification to encourage endothelialization. This study presents a modification of PVA with fucoidan. Fucoidan is a sulfated polysaccharide with anticoagulant and antithrombotic properties, which was shown to potentially increase endothelial cell adhesion and proliferation. By mixing fucoidan with PVA and co-crosslinked by sodium trimetaphosphate (STMP), the modification was achieved without sacrificing mechanical properties. Endothelial cell adhesion and monolayer function were significantly enhanced by the fucoidan modification. In vitro and ex-vivo studies showed low platelet adhesion and activation and decreased thrombin generation with fucoidan modified PVA. The modification proved to be compatible with gamma sterilization. In vivo evaluation of fucoidan modified PVA grafts in rabbits exhibited increased patency rate, endothelialization, and reduced intimal hyperplasia formation. The fucoidan modification presented here benefited the development of PVA vascular grafts and can be adapted to other blood contacting surfaces. [ABSTRACT FROM AUTHOR]

Objective: In the past five decades, many small caliber vascular grafts have been developed as bypasses for infrapopliteal or coronary arteries. However, reliable grafts have not been obtained owing to poor patency, mainly caused by early thrombosis or neointimal hyperplasia in the intermediate period after implantation. We developed a novel small caliber heparin-loaded polyethylene terephthalate ultrafine microfiber (HL-PET) graft and evaluated the feasibility to overcome those main causes of graft failure in canine carotid artery implantation., Methods: The HL-PET graft with a diameter of 3 mm and length of 30 mm was made with combination of three key technologies: (1) weaving with PET ultrafine microfiber with a high biological porosity allowing for cell ingrowth, (2) heparin loading on microfiber surfaces, and (3) an outer coating with a flexible bioabsorbable polymer for prevention of blood leakage and graft kinking. Kink resistance, water permeability, and loaded heparin were assessed. One HL-PET graft each was implanted into a carotid artery of six animals. Graft patency rate and healing were assessed 24 weeks after implantation., Results: Among the six grafts, five were deemed patent (patency rate of >83%), with one occluded 20 weeks after implantation. Histopathology of the patent grafts showed neointima formation with confluent endothelial cell lining (estimated mean endothelial cell coverage area, 89 ± 18%). Intimal hyperplasia at the anastomotic sites and severe chronic inflammatory responses were not observed. Immunohistochemistry with antibodies to endothelial nitric oxide synthase, alpha 2 smooth muscle actin and calponin 1 revealed luminal surface endothelial cell layer with expression of endothelial nitric oxide synthase and vascular smooth muscle cells with contractile phenotype in the subintimal layer., Conclusions: The HL-PET graft showed no early postoperative thrombosis and was able to demonstrate a high patency rate with no severe biological response observed after 24 weeks. These results strongly suggest the potential of the HL-PET graft to be used for distal bypasses., (© 2020 by the Society for Vascular Surgery. Published by Elsevier Inc.)

Recellularization of ex vivo-derived scaffolds remains a significant hurdle primarily due to the scaffolds subcellular pore size that restricts initial cell seeding to the scaffolds periphery and inhibits migration over time. With the aim to improve cell migration, repopulation, and graft mechanics, the effects of a four-step culture approach were assessed. Using an ex vivo-derived vein as a model scaffold, human smooth muscle cells were first seeded onto its ablumen (Step 1: 3 hr) and an aggressive 0-100% nutrient gradient (lumenal flow under hypotensive pressure) was created to initiate cell migration across the scaffold (Step 2: Day 0 to 19). The effects of a prolonged aggressive nutrient gradient created by this single lumenal flow was then compared with a dual flow (lumenal and ablumenal) in Step 3 (Day 20 to 30). Analyses showed that a single lumenal flow maintained for 30 days resulted in a higher proportion of cells migrating across the scaffold toward the vessel lumen (nutrient source), with improved distribution. In Step 4 (Day 31 to 45), the transition from hypotensive pressure (12/8 mmHg) to normotensive (arterial-like) pressure (120/80 mmHg) was assessed. It demonstrated that recellularized scaffolds exposed to arterial pressures have increased glycosaminoglycan deposition, physiological modulus, and Young's modulus. By using this stepwise conditioning, the challenging recellularization of a vein-based scaffold and its positive remodeling toward arterial biomechanics were obtained., (© 2020 John Wiley & Sons, Ltd.)

Front Cover: Blood clots when it contacts foreign surfaces and can result in failure of cardiovascular biomedical devices. Endothelial cells line our native vasculature and are responsible for blood compatibility. Designing materials that foster a functional layer of endothelial cells is a promising strategy for improving their blood compatibility. In the article number 1600574 Daniel E. Heath describes recent advances in the design of polymeric biomaterials that promote endothelialization. [ABSTRACT FROM AUTHOR]

In this paper, we investigate essential mechanical properties and cell behaviors of the scaffolds fabricated by rolling polylactic- co -glycolic acid (PLGA) electrospinning (ES) films for small-diameter vascular grafts (inner diameter < 6 mm). The newly developed strategy can be used to fabricate small diameter vascular grafts with or without pre-seeded cells, which are two main branches for small diameter vascular engineering. We demonstrate that the mechanical properties of our rolling-based scaffolds can be tuned flexibly by the number of layers. For cell-free scaffolds, with the increase of layer number, burst pressure and suture retention increase, elastic tensile modulus maintains unchanged statistically, but compliance and liquid leakage decrease. For cell-containing scaffolds, seeding cells will significantly decrease the liquid leakage, but there are no statistical differences for other mechanical properties; moreover, cells live and proliferate well in the scaffold after a 6-day culture., Competing Interests: The authors declare no conflict of interest.

Objective: To evaluate the biocompatibility and hemocompatibility of an enhanced polytetrafluoroethylene (ePTFE) graft modified with sulfonated silk fibroin (SF) and to compare the patency rate of the modified graft to that of the commercially available unmodified ePTFE graft in a rabbit model., Methods: Twelve SF-modified grafts were used to replace a section of the lower abdominal aortic artery in rabbits, and 10 unmodified ePTFE grafts were used as controls. The patency rates of these grafts were examined according to physical findings, ultrasonic examination, and scanning electron microscopy (SEM)., Results: The patency rates of SF-modified ePTFE grafts on day 3, from day 4 to 3 months, and at 3 months were 100%, 91.7%, and 91.7%, respectively, and these values were higher than those for the unmodified grafts (60.0%, 33.3%, and 20.0%, respectively, with P = 0.029, 0.022, and 0.002, respectively). SEM images of grafts harvested 3 months postoperatively showed that approximately 84% of the inner surface of the SF-modified grafts was covered with endothelial cells growing longitudinally with extensive cell-cell connections. In comparison, endothelial cells covered only approximately 11% of the inner lumen of the unmodified grafts, and the inner surface of these grafts was covered with activated platelets, erythrocytes, and newly formed extracellular matrix. We also have developed a rabbit model to evaluate the patency rate of small diameter vessel graft by replacing the lower abdominal aortic artery with graft., Conclusion: The SF-modified ePTFE graft had a higher patency rate than the unmodified PTFE graft in vivo. In addition, replacement of the rabbit abdominal aortic artery represents a feasible and convenient model for evaluating the patency of small diameter vascular grafts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Microvascular surgery is becoming a prevalent surgical practice. Replantation, hand reconstruction, orthopedic, and free tissue transfer procedures all rely on microvascular surgery for the repair of venous and arterial defects at the millimeter and submillimeter levels. Often, a vascular graft is required for the procedure as a means to bridge the gap between native arteries. While autologous vessels are desired for their bioactivity and non-thrombogenicity, the tedious harvest process, lack of availability, and caliber or mechanical mismatch contribute to graft failure. Thus, there is a need for an off-the-shelf artificial vascular graft that has low thrombogenic properties and mechanical properties matching those of submillimeter vessels. Poly(vinyl alcohol) hydrogel (PVA) has excellent prospects as a vascular graft due to its bioinertness, low thrombogenicity, high water content, and tunable mechanical properties. Here, we fabricated PVA grafts with submillimeter diameter and mechanical properties that closely approximated those of the rabbit femoral artery. In vitro platelet adhesion and microparticle release assay verified the low thrombogenicity of PVA. A stringent proof-of-concept in vivo test was performed by implanting PVA grafts in rabbit femoral artery with multilevel arterial occlusion. Laser Doppler measurements indicated the improved perfusion of the distal limb after implantation with PVA grafts. Moreover, ultrasound Doppler and angiography verified that the submillimeter diameter PVA vascular grafts remained patent for 2 weeks without the aid of anticoagulant or antithrombotics. Endothelial cells were observed in the luminal surface of one patent PVA graft. The advantageous non-thrombogenic and tunable mechanical properties of PVA that are retained even in the submillimeter diameter dimensions support the application of this biomaterial for vascular replacement in microvascular surgery.