Small-diameter Vascular Grafts Research Articles

Bio-composites reinforced with unique coral collagen fibers: Towards biomimetic-based small diameter vascular grafts

Cardiovascular Diseases (CVDs) are the leading cause of death worldwide. Approximately 31% of all global deaths are caused by CVDs, of which 42% are attributable to coronary artery disease (CAD). CAD is characterized by a narrowing of arteries that restricts the normal blood flow. Over time, surgical intervention is required in severe cases of occlusions and includes implantation of autologous vessels. Today synthetic grafts are used successfully as replacements for blood vessels with a diameter larger than 6 mm. However, they often fail as small-diameter blood vessel replacements.This study introduces a new biocomposite material system consisting of unique and long (cm-scale) collagen fibers derived from soft corals embedded within an alginate hydrogel matrix. The new biocomposite layers were used to fabricate grafts, towards developing a new class of tissue-engineered small-diameter blood vessels. These constructs consisted of both circumferentially and longitudinally oriented collagen fibers. The mechanical properties of the grafts were investigated via a new experimental setup constructed in our lab for this purpose, which applied internal pressure levels of 0–300 mmHg. Similar to native coronary arteries, the biocomposite tubes demonstrated a compliance of 4.88 ± 0.99%/100 mmHg for a physiologic pressure range of 80–120 mmHg. Furthermore, a numerical finite element simulation model is proposed to generate the overall mechanical response of the construct. It is composed of axial and circumferential fibers embedded within the continuum alginate elements. Good prediction is demonstrated when compared with the measured pressure-strain response. Moreover, we examined biocompatibility and cell growth on the collagen fibers. Fibroblast cells proliferated during the experiment that lasted for 32 days and showed aligned configuration with the collagen fiber orientation.The novelty of this study is manifested in the use of naturally derived coral-based long collagen fibers for the development of a new class of tissue-engineered grafts. The proposed novel biocomposite graft demonstrated both mechanical and biological compatibility and can be further developed for small-diameter blood-vessel replacement.

Development of Multi-layer Tubular Vascular Scaffold to Enhance Compliance by Exhibiting a Negative Poisson’s Ratio

Synthetic small diameter vascular grafts frequently fail owing to intimal hyperplasia, results from mismatched compliance between the vascular graft and native vessels. A vascular graft with a negative Poisson's ratio (NPR, materials expand transversely when pulled axially) was suggested to enhance compliance. We produced a three-layer tubular vascular scaffold with NRP properties. The luminal side consisted of nanosized electrospun fibers for endothelial cell (EC) growth. The middle layer was an NPR structure created using 3D printing, and the outer layer was a microsized electrospun fiber layer for vascular smooth muscle cell (VSMC) growth. The developed multi-layer tubular vascular scaffold contained NPR value. And the NPR vascular scaffold showed 1.7 time higher compliance than the PPR scaffold and 3.8 times higher than that of commercial polytetrafluoroethylene (PTFE) vascular graft. In addition, the ECs and VSMCs were well survived and proliferated on the scaffold during 10 days of culture. From the optimized co-culture condition of the VSMCs and ECs that VSMC phenotype changed was inhibited, we successfully generated a thin luminal layer, which consisted of ECs and the proper thickness of the VSMC layer under the ECs. This scaffold may have a potential to replace conventional artificial vascular graft by providing enhanced compliance and improved cell culture environment.

Electrospinning of small diameter vascular grafts with preferential fiber directions and comparison of their mechanical behavior with native rat aortas

Conventional electrospun small diameter vascular grafts have a random fiber orientation. In order to achieve mechanical characteristics similar to a native blood vessel, a controllable fiber orientation is of interest. In this study the electrospinning jet was directly controlled by means of an auxiliary, changeable electrostatic field, so that the fibers could be deposited in adjustable orientations. Prostheses with circumferentially, axially, fenestrated and randomly aligned fibers were electrospun on Ø2mm mandrels out of a thermoplastic polyurethane (PUR) and a polylactid acid (PLLA). The impact of the materials and the various preferential fiber orientations on the resulting biomechanics was investigated and compared with that of the native rat aorta in quasistatic and dynamic hoop tensile tests. The test protocol included 3000 dynamic loading cycles in the physiological blood pressure range and ended with a quasistatic tensile test. Any orientation of the fibers in a particular direction resulted in a significant reduction in scaffold porosity for both materials. The standard randomly oriented PUR grafts showed the highest compliance of 29.7 ± 5.5 [%/100 mmHg] and were thus closest to the compliance of the rat aortas, which was 37.2 ± 6.5 [%/100 mmHg]. The maximum tensile force was increased at least 6 times compared to randomly spun grafts by orienting the fibers in the circumferential direction. During the 3000 loading cycles, creeping of the native rat aorta was below 1% whereas the electrospun grafts showed creeping up to 2.4 ± 1.2%. Although the preferred fiber orientations were only partially visible in the scanning electron micrographs, the mechanical effects were evident. The investigations suggest a multi-layer wall structure of the vascular prosthesis, since none of the preferred fiber directions and the materials used could imitate the typical j-shaped mechanical characteristics of the rat aorta.

Endothelial Cell-Mediated Gene Delivery for In Situ Accelerated Endothelialization of a Vascular Graft.

As an urgently needed device for vascular diseases, the small-diameter vascular graft is limited by high thrombogenicity in clinical applications. Rapid endothelialization is a promising approach to construct an antithrombogenic inner surface of the vascular graft. The main bottleneck for rapid endothelialization is the adhesion, migration, and proliferation of endothelial cells (ECs) in situ of the small-diameter vascular graft. Herein, we innovatively fabricated an intelligent gene delivery small-caliber vascular graft based on electrospun poly(lactic acid-co-caprolactone) and gelatin for rapid in situ endothelialization. The graft surface was co-modified with EC adhesive peptide of Arg-Glu-Asp-Val (REDV) and responsive gene delivery system. REDV can selectively adhere ECs onto the graft surface; subsequently, the overexpressed matrix metalloproteinase by ECs can effectively cleave the linker peptide GPQGIWGQ-C; and finally, the gene complexes were intelligently and enzymatically released from the graft surface, and thereby, the gene can efficiently transfect ECs. Importantly, this enzymatically releasing gene surface has been proven to be safe and temporarily stable in blood flow owing to the biotin-avidin interaction to immobilize gene complexes on the inner surface of vascular grafts through the GPQGIWGQ-C peptide linker. It has the advantage of specifically adhering the ECs to the surface and smartly transfecting them with high transfection efficiency. The co-modified surface has been demonstrated to accelerate the luminal endothelialization in vivo, which might be attributed to the synergistic effect of REDV and effective gene transfection. Particularly, the intelligent and responsive gene release surface will open a new avenue to enhance the endothelialization of blood-contacting devices.

Review: Tissue Engineering of Small-Diameter Vascular Grafts and Their In Vivo Evaluation in Large Animals and Humans.

To date, a wide range of materials, from synthetic to natural or a mixture of these, has been explored, modified, and examined as small-diameter tissue-engineered vascular grafts (SD-TEVGs) for tissue regeneration either in vitro or in vivo. However, very limited success has been achieved due to mechanical failure, thrombogenicity or intimal hyperplasia, and improvements of the SD-TEVG design are thus required. Here, in vivo studies investigating novel and relative long (10 times of the inner diameter) SD-TEVGs in large animal models and humans are identified and discussed, with emphasis on graft outcome based on model- and graft-related conditions. Only a few types of synthetic polymer-based SD-TEVGs have been evaluated in large-animal models and reflect limited success. However, some polymers, such as polycaprolactone (PCL), show favorable biocompatibility and potential to be further modified and improved in the form of hybrid grafts. Natural polymer- and cell-secreted extracellular matrix (ECM)-based SD-TEVGs tested in large animals still fail due to a weak strength or thrombogenicity. Similarly, native ECM-based SD-TEVGs and in-vitro-developed hybrid SD-TEVGs that contain xenogeneic molecules or matrix seem related to a harmful graft outcome. In contrast, allogeneic native ECM-based SD-TEVGs, in-vitro-developed hybrid SD-TEVGs with allogeneic banked human cells or isolated autologous stem cells, and in-body tissue architecture (IBTA)-based SD-TEVGs seem to be promising for the future, since they are suitable in dimension, mechanical strength, biocompatibility, and availability.

Photooxidation crosslinking to recover residual stress in decellularized blood vessel.

Decellularization method based on trypsin-digestion is widely used to construct small diameter vascular grafts. However, this method will reduce the opening angle of the blood vessel and result in the reduction of residual stress. Residual stress reduced has an adverse effect on the compliance and permeability of small diameter vascular grafts. To improve the situation, acellular blood vessels were treated with glutaraldehyde and photooxidation crosslinking respectively, and the changes of opening angle, circumferential residual strain of native blood vessels, decellularized arteries and crosslinked blood vessels were measured by means of histological examination, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) in this study. The opening angle of decellularized arteries significantly restored after photooxidation crosslinking (P = 0.0216), while that of glutaraldehyde crosslinking blood vessels reduced. The elastic fibers inside the blood vessels became densely rearranged after photooxidation crosslinking. The results of finite element simulation showed that the residual stress increased with the increase of opening angle. In this study, we found at the first time that photooxidation crosslinking method could significantly increase the residual stress of decellularized vessels, which provides biomechanical support for the development of new biomaterials of vascular grafts.

Evaluation of small-diameter silk vascular grafts implanted in dogs

ObjectivesVascular replacement is one treatment for cardiovascular disease. However, in blood vessels with a diameter less than 6 mm, the existing artificial vascular grafts may be occluded by thrombus formation or intimal hyperplasia. Thus, new artificial vascular grafts need to be developed. We have developed a small-diameter artificial vascular graft made of silk fibroin. The implantation of such graft has been evaluated mainly in rats. However, only a few reports describe long-term implantation in large animal models. Therefore, modified silk fibroin artificial vascular grafts were implanted in the femoral arteries of dogs, and their patency and remodeling ability were investigated. MethodsSix beagles weighing 10 to 12 kg were used for the in vivo study. Grafts (4 cm length × 3.5 mm inner diameter) were implanted in the femoral artery of 6 dogs. The patency of the graft was monitored using vascular ultrasound apparatus. At 3 months', 5 months', and 1-year postimplantation, the graft was retrieved and conducted histopathologic examination. ResultsNo side effects, such as ischemia, paralysis, and edema of the hind legs, were observed postimplantation. Five of the 6 grafts exhibited a high patency rate, and the lumen was covered with vascular endothelial cells in the central part of the graft 3 months’ postimplantation. ConclusionsBased on these results, artificial silk fibroin vascular grafts implanted in the femoral arteries of dogs exhibit high patency and remodeling ability. Silk fibroin grafts may be clinically applicable as an artificial vascular graft in small-diameter <6 mm.

Evaluation of human umbilical vein endothelial cells growth onto heparin-modified electrospun vascular grafts

One of the main challenges of cardiovascular tissue engineering is the development of bioresorbable and compliant small-diameter vascular grafts (SDVG) for patients where autologous grafts are not an option. In this work, electrospun bilayered bioresorbable SDVG based on blends of poly(L-lactic acid) (PLLA) and segmented polyurethane (PHD) were prepared and evaluated. The inner layer of these SDVG was surface-modified with heparin, following a methodology involving PHD urethane functional groups. Heparin was selected as anticoagulant agent, and also due to its ability to promote human umbilical vein endothelial cells (HUVECs) growth and to inhibit smooth muscle cells over-proliferation, main cause of neointimal hyperplasia and restenosis. Immobilized heparin was quantified and changes in SDVG microstructure were investigated through SEM. Tensile properties of the heparin-functionalized SDVG resembled those of saphenous vein. Vascular grafts were seeded with HUVECs and cultured on a flow-perfusion bioreactor to analyze the effect of heparin on graft endothelization under simulated physiological-like conditions. The analysis of endothelial cells attachment and gene expression (Real-Time PCR) pointed out that the surface functionalization with heparin successfully promoted a stable and functional endothelial cell layer.

The effect of hypoxia-mimicking responses on improving the regeneration of artificial vascular grafts

Cellular transition to hypoxia following tissue injury, has been shown to improve angiogenesis and regeneration in multiple tissues. To take advantage of this, many hypoxia-mimicking scaffolds have been prepared, yet the oxygen access state of implanted artificial small-diameter vascular grafts (SDVGs) has not been investigated. Therefore, the oxygen access state of electrospun PCL grafts implanted into rat abdominal arteries was assessed. The regions proximal to the lumen and abluminal surfaces of the graft walls were normoxic and only the interior of the graft walls was hypoxic. In light of this differential oxygen access state of the implanted grafts and the critical role of vascular regeneration on SDVG implantation success, we investigated whether modification of SDVGs with HIF-1α stabilizer dimethyloxalylglycine (DMOG) could achieve hypoxia-mimicking responses resulting in improving vascular regeneration throughout the entirety of the graft wall. Therefore, DMOG-loaded PCL grafts were fabricated by electrospinning, to support the sustained release of DMOG over two weeks. In vitro experiments indicated that DMOG-loaded PCL mats had significant biological advantages, including: promotion of human umbilical vein endothelial cells (HUVECs) proliferation, migration and production of pro-angiogenic factors; and the stimulation of M2 macrophage polarization, which in-turn promoted macrophage regulation of HUVECs migration and smooth muscle cells (SMCs) contractile phenotype. These beneficial effects were downstream of HIF-1α stabilization in HUVECs and macrophages in normoxic conditions. Our results indicated that DMOG-loaded PCL grafts improved endothelialization, contractile SMCs regeneration, vascularization and modulated the inflammatory reaction of grafts in abdominal artery replacement models, thus promoting vascular regeneration.

Effect of sequential electrospinning and co-electrospinning on morphological and fluid mechanical wall properties of polycaprolactone and bovine gelatin scaffolds, for potential use in small diameter vascular grafts

BackgroundNowadays, 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.MethodologyFor 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.ResultsIt 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.ConclusionThis 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.

Changing compliance of poly(vinyl alcohol) tubular scaffold for vascular graft applications through modifying interlayer adhesion and crosslinking density.

Poly(vinyl alcohol) (PVA) is a water-soluble polymer and forms a hydrogel that has been studied as a potential small-diameter (<6 mm) vascular graft implant. The PVA hydrogel crosslinked using sodium trimetaphosphate (STMP) has been shown to have many beneficial properties such as bioinert, low-thrombogenicity, and easy surface modification. Compared to conventional synthetic vascular graft materials, PVA has also shown to possess better mechanical properties; however, the compliance and other mechanical properties of PVA grafts are yet to be optimized compared to the native blood vessels. Mechanical compliance has been an important parameter to be studied for small-diameter vascular grafts, as compliance has been proposed to play an important role in intimal hyperplasia formation. PVA grafts are made using dip-casting a cylindrical mold into crosslinking solution. The number of dipping can be used to control the wall thickness of the resulting PVA grafts. In this study, we hypothesized that the number of dip layer and wall thickness, the chemical crosslinking, and interlayer adhesive strength could be important parameters in the fabrication process that would affect compliance. This work provides the relationship between the wall thickness, burst pressure, and compliance of PVA. Furthermore, our data showed that interlayer adhesion as well as chemical and physical crosslinking density can increase the compliance of PVA grafts.

Heparinization and hybridization of electrospun tubular graft for improved endothelialization and anticoagulation

Constructing biomimetic structure and immobilizing antithrombus factors are two effective methods to ensure rapid endothelialization and long-term anticoagulation for small-diameter vascular grafts. However, few literatures are available regarding simultaneous implementation of these two strategies. Herein, a nano-micro-fibrous biomimetic graft with a heparin coating was prepared via a step-by-step in situ biosynthesis method to improve potential endothelialization and anticoagulation. The 4-mm-diameter tubular graft consists of electrospun cellulose acetate (CA) microfibers and entangled bacterial nanocellulose (BNC) nanofibers with heparin coating on dual fibers. The hybridized and heparinized graft possesses suitable pore structure that facilitates endothelia cells adhesion and proliferation but prevents infiltration of fibrous tissue and blood leakage. In addition, it shows higher mechanical properties than those of bare CA and hybridized CA/BNC grafts, which match well with native blood vessels. Moreover, this dually modified graft exhibits improved blood compatibility and endothelialization over the counterparts without hybridization or heparinization according to the testing results of platelet adhesion, cell morphology, and protein expression of von Willebrand Factor. This novel graft with dual modifications shows promising as a new small-diameter vascular graft. This study provides a guidance for promoting endothelialization and blood compatibility by dual modifications of biomimetic structure and immobilized bioactive molecules.

Basement Membrane of Small Diameter Xenogeneic Extracellular Matrix Scaffolds Modulate Quiescent Human Endothelial Cell Monolayer Formation

Off-the shelf small diameter vascular grafts are an attractive alternative to eliminate the need and shortcomings of autologous tissue for vascular grafting. Bovine saphenous vein (SV) extracellular matrix (ECM) scaffolds are potentially ideal small diameter vascular grafts, due to their inherit architecture and signaling molecules capable of driving proper cell behavior and regeneration. However, harnessing this potential is predicated on the ability of the scaffold generation technique to maintain the delicate structure, composition and associated function of native vascular ECM. Previous decellularization methods have been uniformly demonstrated to distupt the delicate basement membrane (BM) components of native vascular ECM. Here we demonstrate bovine SV ECM scaffolds generated using the novel antigen removal (AR) approach results in retention of native BM protein composition (e.g., Collagen IV and laminin), structure and cell modulatory function. Presence of BM proteins in AR vascular ECM scaffolds increases endothelial cell migration and proliferation, appropriate formation of adherence junction and apicobasal polarization, increased secretion of nitric oxide, and modulates endothelial cell quiescence. We conclude that presence of intact native vascular BM in AR SV ECM scaffolds modulate human endothelial cell behaviors which are essential for vessel homeostasis.

Tissue Engineered Bovine Saphenous Vein Extracellular Matrix Scaffolds Produced Via Antigen Removal Achieve High &lt;i&gt;In Vivo&lt;/i&gt; 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.

Behaviour of Vascular Smooth Muscle Cells on Amine Plasma-Coated Materials with Various Chemical Structures and Morphologies.

Amine-coated biodegradable materials based on synthetic polymers have a great potential for tissue remodeling and regeneration because of their excellent processability and bioactivity. In the present study, we have investigated the influence of various chemical compositions of amine plasma polymer (PP) coatings and the influence of the substrate morphology, represented by polystyrene culture dishes and polycaprolactone nanofibers (PCL NFs), on the behavior of vascular smooth muscle cells (VSMCs). Although all amine-PP coatings improved the initial adhesion of VSMCs, 7-day long cultivation revealed a clear preference for the coating containing about 15 at.% of nitrogen (CPA-33). The CPA-33 coating demonstrated the ideal combination of good water stability, a sufficient amine group content, and favorable surface wettability and morphology. The nanostructured morphology of amine-PP-coated PCL NFs successfully slowed the proliferation rate of VSMCs, which is essential in preventing restenosis of vascular replacements in vivo. At the same time, CPA-33-coated PCL NFs supported the continuous proliferation of VSMCs during 7-day long cultivation, with no significant increase in cytokine secretion by RAW 264.7 macrophages. The CPA-33 coating deposited on biodegradable PCL NFs therefore seems to be a promising material for manufacturing small-diameter vascular grafts, which are still lacking on the current market.

Future Perspectives in Small-Diameter Vascular Graft Engineering.

The increased demands of small-diameter vascular grafts (SDVGs) globally has forced the scientific society to explore alternative strategies utilizing the tissue engineering approaches. Cardiovascular disease (CVD) comprises one of the most lethal groups of non-communicable disorders worldwide. It has been estimated that in Europe, the healthcare cost for the administration of CVD is more than 169 billion €. Common manifestations involve the narrowing or occlusion of blood vessels. The replacement of damaged vessels with autologous grafts represents one of the applied therapeutic approaches in CVD. However, significant drawbacks are accompanying the above procedure; therefore, the exploration of alternative vessel sources must be performed. Engineered SDVGs can be produced through the utilization of non-degradable/degradable and naturally derived materials. Decellularized vessels represent also an alternative valuable source for the development of SDVGs. In this review, a great number of SDVG engineering approaches will be highlighted. Importantly, the state-of-the-art methodologies, which are currently employed, will be comprehensively presented. A discussion summarizing the key marks and the future perspectives of SDVG engineering will be included in this review. Taking into consideration the increased number of patients with CVD, SDVG engineering may assist significantly in cardiovascular reconstructive surgery and, therefore, the overall improvement of patients’ life.

Expanded polytetrafluoroethylene/silk fibroin/salicin vascular graft fabrication for improved endothelialization and anticoagulation

Clinical application of small-diameter artificial vascular grafts has been hampered by intimal blockages owing to the lack of an endothelial layer and the formation of thrombosis. In this study, an expanded polytetrafluoroethylene (ePTFE) vascular graft was fabricated using a biofriendly ethanol/water mixture as a lubricant and drug carrier. Natural silk fibroin (SF) hydrogel and white willow extract salicin were embedded into ePTFE graft successfully via the ethanol/water lubricant and drug carrier as verified by Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The ePTFE graft functionalized by SF hydrogel improved the proliferation of human umbilical vein endothelial cell (HUVEC) due to SF’s hydrophilia and cytocompatibility as measured by the live/dead and cell counting kit-8 (CCK-8) assays. The rapid endothelialization of ePTFE graft helped reduced intimal blockages in vitro. Furthermore, the salicin-modified ePTFE graft exhibited an anticoagulation property as demonstrated by platelet adhesion and activated partial thromboplastin time (APTT) tests. These results suggest that ePTFE graft fabricated with silk fibroin and salicin can be an attractive candidate for vascular grafts.

Coaxial-printed small-diameter polyelectrolyte-based tubes with an electrostatic self-assembly of heparin and YIGSR peptide for antithrombogenicity and endothelialization

Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation. Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios, it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization. Herein, on basis of 3D-printed polyelectrolyte-based vascular grafts, a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described. A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles, in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used. Further, dual bioactive molecules, heparin with negative charges and Tyr-Ile-Gly-Ser-Arg (YIGSR) peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes. Due to the electrostatic interaction, the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization. This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction, revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.

Extracellular Matrix for Small-Diameter Vascular Grafts.

To treat coronary heart disease, coronary artery bypass grafts are used to divert blood flow around blockages in the coronary arteries. Autologous grafts are the gold standard of care, but they are characterized by their lack of availability, low quality, and high failure rates. Alternatively, tissue-engineered small-diameter vascular grafts made from synthetic or natural polymers have not demonstrated adequate results to replace autologous grafts; synthetic grafts result in a loss of patency due to thrombosis and intimal hyperplasia, whereas scaffolds from natural polymers are generally unable to support the physiological conditions. Extracellular matrix (ECM) from a variety of sources, including cell-derived, 2D, and cannular tissues, has become an increasingly useful tool for this application. The current review examines the ECM-based methods that have recently been investigated in the field and comments on their viability for clinical applications.

Bilayer nicorandil-loaded small-diameter vascular grafts improve endothelial cell function via PI3K/AKT/eNOS pathway

For the surgical treatment of cardiovascular disease (CVD), there is a clear and unmet need in developing small-diameter (diameter < 6 mm) vascular grafts. In our previous work, sulfated silk fibroin (SF) was successfully fabricated as a potential candidate for preparing vascular grafts due to the great cytocompatibility and hemocompatibility. However, vascular graft with single layer is difficult to adapt to the complex internal environment. In this work, polycaprolactone (PCL) and sulfated SF were used to fabricate bilayer vascular graft (BLVG) to mimic the structure of natural blood vessels. To enhance the biological activity of BLVG, nicorandil (NIC), an FDA-approved drug with multi-bioactivity, was loaded in the BLVG to fabricate NIC-loaded BLVG. The morphology, chemical composition and mechanical properties of NIC-loaded BLVG were assessed. The results showed that the bilayer structure of NIC-loaded BLVG endowed the graft with a biphasic drug release behavior. The in vitro studies indicated that NIC-loaded BLVG could significantly increase the proliferation, migration and antioxidation capability of endothelial cells (ECs). Moreover, we found that the potential biological mechanism was the activation of PI3K/AKT/eNOS signaling pathway. Overall, the results effectively demonstrated that NIC-loaded BLVG had a promising in vitro performance as a functional small-diameter vascular graft.