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Combining synthetic polymers and biomacromolecules prevents the occurrence of thrombogenicity and intimal hyperplasia in small-diameter vascular grafts (SDVGs). In the present study, an electrospinning poly (L)-lactic acid (PLLA) bilayered scaffold is developed to prevent thrombosis after implantation by promoting the capture and differentiation of endothelial colony-forming cells (ECFCs). The scaffold consists of an outer PLLA scaffold and an inner porous PLLA biomimetic membrane combined with heparin (Hep), peptide Gly-Gly-Gly-Arg-Glu-Asp-Val (GGG-REDV), and vascular endothelial growth factor (VEGF). Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and contact angle goniometry were performed to determine successful synthesis. The tensile strength of the outer layer was obtained using the recorded stress/strain curves, and hemocompatibility was evaluated using the blood clotting test. The proliferation, function, and differentiation properties of ECFCs were measured on various surfaces. Scanning electronic microscopy (SEM) was used to observe the morphology of ECFCs on the surface. The outer layer of scaffolds exhibited a similar strain and stress performance as the human saphenous vein via the tensile experiment. The contact angle decreased continuously until it reached 56° after REDV/VEGF modification, and SEM images of platelet adhesion showed a better hemocompatibility surface after modification. The ECFCs were captured using the REDV + VEGF + surface successfully under flow conditions. The expression of mature ECs was constantly increased with the culture of ECFCs on REDV + VEGF + surfaces. SEM images showed that the ECFCs captured by the REDV + VEGF + surface formed capillary-like structures after 4 weeks of culture. The SDVGs modified by REDV combined with VEGF promoted ECFC capture and rapid differentiation into ECs, forming capillary-like structures in vitro. The bilayered SDVGs could be used as vascular devices that achieved a high patency rate and rapid re-endothelialization.

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Vascular regeneration and patency maintenance, without anticoagulant administration, represent key developmental trends to enhance small-diameter vascular grafts (SDVG) performance. In vivo engineered autologous biotubes have emerged as SDVG candidates with pro-regenerative properties. However, mechanical failure coupled with thrombus formation hinder translational prospects of biotubes as SDVGs. Previously fabricated poly(ε-caprolactone) skeleton-reinforced biotubes (PBs) circumvented mechanical issues and achieved vascular regeneration, but orally administered anticoagulants were required. Here, highly efficient and biocompatible functional modifications were introduced to living cells on PB lumens. The 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (DMPE)-PEG-conjugated anti-coagulant bivalirudin (DPB) and DMPE-PEG-conjugated endothelial progenitor cell (EPC)-binding TPS-peptide (DPT) modifications possessed functionality conducive to promoting vascular graft patency. Co-modification of DPB and DPT swiftly attained luminal saturation without influencing cell viability. DPB repellent of non-specific proteins, DPB inhibition of thrombus formation, and DPB protection against functional masking of DPT's EPC-capture by blood components, which promoted patency and rapid endothelialization in rat and canine artery implantation models without anticoagulant administration. This strategy offers a safe, facile, and fast technical approach to convey additional functionalization to living cells within tissue-engineered constructs.

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Magnesium alloy stents have been extensively studied in the field of biodegradable metal stents due to their exceptional biocompatibility, biodegradability and excellent biomechanical properties. Nevertheless, the specific in vivo service environment causes magnesium alloy stents to degrade rapidly and fail to provide sufficient support for a certain time. Compared to previous reviews, this paper focuses on presenting an overview of the development history, the key issues, mechanistic analysis, traditional protection strategies and new directions and protection strategies for magnesium alloy stents. Alloying, optimizing stent design and preparing coatings have improved the corrosion resistance of magnesium alloy stents. Based on the corrosion mechanism of magnesium alloy stents, as well as their deformation during use and environmental characteristics, we present some novel strategies aimed at reducing the degradation rate of magnesium alloys and enhancing the comprehensive performance of magnesium alloy stents. These strategies include adapting coatings for the deformation of the stents, preparing rapid endothelialization coatings to enhance the service environment of the stents, and constructing coatings with self-healing functions. It is hoped that this review can help readers understand the development of magnesium alloy cardiovascular stents and solve the problems related to magnesium alloy stents in clinical applications at the early implantation stage.

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Magnesium (Mg) and its alloys, as potential biodegradable materials, have drawn wide attention in the cardiovascular stent field because of their appropriate mechanical properties and biocompatibility. Nevertheless, the occurrence of thrombosis, inflammation, and restenosis of implanted Mg alloy stents caused by their poor corrosion resistance and insufficient endothelialization restrains their anticipated clinical applications. Numerous surface treatment tactics have mainly striven to modify the Mg alloy for inhibiting its degradation rate and enduing it with biological functionality. This review focuses on highlighting and summarizing the latest research progress in functionalized coatings on Mg alloys for cardiovascular stents over the last decade, regarding preparation strategies for metal oxide, metal hydroxide, inorganic nonmetallic, polymer, and their composite coatings; and the performance of these strategies in regulating degradation behavior and biofunction. Potential research direction is also concisely discussed to help guide biological functionalized strategies and inspire further innovations. It is hoped that this review can give assistance to the surface modification of cardiovascular Mg-based stents and promote future advancements in this emerging research field.

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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.

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Rapid endothelialization of small-diameter vascular grafts remains a significant challenge in clinical practice. In addition, compliance mismatch causes intimal hyperplasia and finally leads to graft failure. To achieve compliance match and rapid endothelialization, we synthesized low-initial-modulus poly(ester-urethane)urea (PEUU) elastomer and prepared it into electrospun tubular grafts and then functionalized the grafts with poly(ethylene glycol) (PEG) and heparin via covalent grafting. The PEG- and heparin-functionalized PEUU (PEUU@PEG-Hep) graft had comparable mechanical properties with the native blood vessel. In vitro data demonstrated that the grafts are of good cytocompatibility and blood compatibility. Covalent grafting of PEG and heparin significantly promoted the adhesion, spreading, and proliferation of human umbilical vein endothelial cells (HUVECs) and upregulated the expression of vascular endothelial cell-related genes, as well as increased the capability of grafts in preventing platelet deposition. In vivo assessments indicated good biocompatibility of the PEUU@PEG-Hep graft as it did not induce severe immune responses. Replacement of resected carotid artery with the PEUU@PEG-Hep graft in a rabbit model showed that the graft was capable of rapid endothelialization, initiated vascular remodeling, and maintained patency. This study demonstrates the PEUU@PEG-Hep vascular graft with compliance match and efficacious antithrombosis might find opportunities for bioactive blood vessel substitutes.

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Stimulated by the leading mortalities of cardiovascular diseases (CVDs), various types of cardiovascular biomaterials have been widely investigated in the past few decades. Although great therapeutic effects can be achieved by bare metal stents (BMS) and drug-eluting stents (DES) within months or years, the long-term complications such as late thrombosis and restenosis have limited their further applications. It is well accepted that rapid endothelialization is a promising approach to eliminate these complications. Convincing evidence has shown that endothelial progenitor cells (EPCs) could be mobilized into the damaged vascular sites systemically and achieve endothelial repair in situ, which significantly contributes to the re-endothelialization process. Therefore, how to effectively capture EPCs via specific molecules immobilized on biomaterials is an important point to achieve rapid endothelialization. Further, in the context of predictive, preventive, personalized medicine (PPPM), the abnormal number alteration of EPCs in circulating blood and certain inflammation responses can also serve as important indicators for predicting and preventing early cardiovascular disease. In this contribution, we mainly focused on the following sections: the definition and classification of EPCs, the mechanisms of EPCs in treating CVDs, the potential diagnostic role of EPCs in predicting CVDs, as well as the main strategies for cardiovascular biomaterials to capture EPCs.

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Establishing and maintaining a healthy endothelium on vascular and intravascular devices is crucial for the prevention of thrombosis and stenosis. Generating a biofunctional surface on vascular devices to recruit endothelial progenitor cells (EPCs) and endothelial cells (ECs) has proven efficient in promoting in situ endothelialization. However, molecules conventionally used for EPC/EC capturing generally lack structural stability, capturing specificity, and biological functionalities, which have limited their applications. Discovery of effective, specific, and structurally stable EPC/EC capturing ligands is desperately needed. Using the high-throughput One-Bead One-Compound combinatorial library screening technology, we recently identified a disulfide cyclic octa-peptide LXW7 (cGRGDdvc), which possesses strong binding affinity and functionality to EPCs/ECs, weak binding to platelets, and no binding to inflammatory cells. Because LXW7 is cyclic and 4 out of the 8 amino acids are unnatural D-amino acids, LXW7 is highly proteolytically stable. In this study, we applied LXW7 to modify small diameter vascular grafts using a Click chemistry approach. In vitro studies demonstrated that LXW7-modified grafts significantly improved EPC attachment, proliferation and endothelial differentiation and suppressed platelet attachment. In a rat carotid artery bypass model, LXW7 modification of the small diameter vascular grafts significantly promoted EPC/EC recruitment and rapidly achieved endothelialization. At 6 weeks after implantation, LXW7-modified grafts retained a high patency of 83%, while the untreated grafts had a low patency of 17%. Our results demonstrate that LXW7 is a potent EPC/EC capturing and platelet suppressing ligand and LXW7-modified vascular grafts rapidly generate a healthy and stable endothelial interface between the graft surface and the circulation to reduce thrombosis and improve patency. STATEMENT OF SIGNIFICANCE: In this study, One-Bead One-Compound (OBOC) technology has been applied for the first time in discovering bioactive ligands for tissue regeneration applications. Current molecules used to modify artificial vascular grafts generally lack EPC/EC capturing specificity, biological functionalities and structural stability. Using OBOC technology, we identified LXW7, a constitutionally stable disulfide cyclic octa-peptide with strong binding affinity and biological functionality to EPCs/ECs, very weak binding to platelets and no binding to inflammatory cells. These characteristics are crucial for promoting rapid endothelialization to prevent thrombosis and improve patency of vascular grafts. LXW7 coating technology could be applied to a wide range of vascular and intravascular devices, including grafts, stents, cardiac valves, and catheters, where a "living" endothelium and healthy blood interface are needed.

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Clinical application of the amniotic membrane (AM) in vascular reconstruction was limited by poor processability, rapid biodegradation, and insufficient hemocompatibility. In this work, decellularized AM was digested to a thermosensitive hydrogel and densely cross-linked in the nanoscale as "enhanced" collagenous fibers. Via N-(3-dimehylaminopropyl)-N'-ethylcarbodiimide and N-hydroxysuccinimide (EDC/NHS) catalysis, REDV was further grafted to simulate anticoagulant substances on naturally derived blood vessels. This modification approach endowed AM with rapid endothelialization and rare vascular restenosis. Through adjusting the fixation condition, the pore size and mechanical stability of the fiber network were approximate to those of natural tissues and precisely designed to fit for cell adhesion. AM was synchronously fixed by alginate dialdehyde (ADA) and EDC/NHS, forming a "double-cross-linked" stable structure with significantly improved mechanical strength and resistance against enzymic degradation. The hemolytic and platelet adhesion test indicated that ADA/REDV-AM could inhibit hemolysis and coagulation. It also exhibited excellent cytocompatibility. It selectively accelerated adsorption and migration of endothelial cells (ECs) while impeding adhesion and proliferation of smooth muscle cells (SMCs). It maintained EC superiority in competitive growth and avoided thrombosis in vivo. Furthermore, its property of promoting reconstruction and repair of blood vessels was proved in an animal experiment. Overall, the present study demonstrates that ADA/REDV-AM has potential application as a small-diameter artificial vascular intima with rapid endothelialization and reduced SMC/platelet adhesion.

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Thrombus and restenosis are two main factors that cause the failure of vascular implants. Constructing a functional and confluent layer of endothelial cells (ECs) is considered an ideal method to prevent these problems. However, oxidative stress induced by the disease and implantation can damage ECs and hinder the endothelialization of implants. Thus, developing biomaterials that can protect ECs adhesion and proliferation from oxidative stress is urgently needed for the rapid endothelialization of vascular implants. In this work, a novel polyurethane (PU-TBN) is synthesized by employing tetramethylpyrazine-nitrone (TBN) as end-group to endow polymers with dual functions of antioxidant activity and promoting endothelialization. Common PU without TBN is also prepared to be control. Compared to PU, PU-TBN significantly promotes human umbilical vein endothelial cells (HUVECs) adhesion and proliferation, where cells spread well and a confluent endothelial layer is formed. PU-TBN also shows obvious free radical scavenging activity, and thus effectively attenuates oxidative stress to protect HUVECs from oxidative apoptosis. Moreover, PU-TBN exhibits enhanced antiplatelets effect, excellent biocompatibility, and similar mechanical properties to PU. These characteristics can endow PU-TBN with great potential to be used as vascular implants or coatings of other materials for rapid endothelialization under complex oxidative stress environment.

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Capture of endothelial progenitor cells (EPCs) in situ has been considered as a promising strategy for the rapid endothelialization and long-term patency of artificial blood vessels and implant devices. In this study, a CD133+ EPC capture surface was fabricated by grafting CD133 antibody (a more specific EPC surface marker than CD34) and Arg-Glu-Asp-Val (REDV) peptideon the methacrylate-grafted hyaluronic acid (MA-HA) and heparin-hybridized (MA-HA&Heparin) resisting layer. Vascular endothelial growth factor (VEGF) was further conjugated to the immobilized heparin. This engineered surface showed good hemocompatibility and significantly higher ability of capturing CD133+ EPCs from human peripheral blood mononuclear cells (PBMCs) and obviously upregulated the expression of endothelial cell (EC) marker genes of EPCs such as VEGF receptor 2 (VEGFR2), CD31, VE-cadherin, and von Willebrand factor (vWF), facilitating the differentiation of EPCs into ECs. The dramatically enhanced EPC proliferation on this surface was dependent on the integrin-VEGFR synergistic signaling, as ERK1/2 phosphorylation was only significantly enhanced on the REDV and VEGF co-immobilized surface. This study highlights a new surface coating strategy for blood-contact materials based on the specific EPC capturing and rapid endothelialization. STATEMENT OF SIGNIFICANCE: Capture of endothelial progenitor cells (EPCs) in situ is a promising strategy for the rapid endothelialization and long-term patency of artificial blood vessels and scaffolds. More specific capture of EPCs by targeting CD133 rather than CD34 can better reduce the risk of inflammation and restenosis. On the other hand, an appropriate microenvironment for EPC proliferation is equally important for endothelialization, which is rarely considered by the existing EPC capture strategies. In this study, the capture ratio of EPCs was significantly increased by simultaneously grafting CD133 antibody and VEGF on a MA-HA and heparin-hybridized antifouling layer. Further, proliferation of EPCs after capture was significantly promoted by grafting VEGF and REDV peptide through the integrin-VEGFR synergistic signaling. This study highlights a new strategy for the surface coating of blood-contact materials based on specific EPC capture and rapid endothelialization.

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Studies have shown that salvianolic acid B (SAB), which is derived from Chinese salvia ( Salvia miltiorrhiza), a plant used in traditional Chinese medicine, can promote the proliferation and migration of endothelial cells. The inner layer of an artificial vascular graft was fabricated using the coaxial electrospinning method and was loaded with the anticoagulant heparin and SAB. The release of heparin and SAB was sustained for almost 30 days and without an initial burst release of SAB. Furthermore, the combined effect of SAB and heparin contributed to promoting human umbilical vein endothelial cell (HUVEC) growth and improved the blood compatibility of the graft. In addition, upregulation of GRP78 by SAB protected human endothelial cells from oxidative stress-induced cellular damage. In vivo evaluation through Masson's trichrome and H&E staining was performed after the graft was subcutaneously embedded in SD rats for 2 weeks and indicated that the graft possessed satisfactory biocompatibility and did not cause a significant immune response. Hence, the functional inner layer is promising for preventing acute thrombosis and promotes rapid endothelialization of artificial vascular grafts.

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The lack of living endothelial cells (ECs) functional layer is one of the major reasons which account for thrombosis of synthetic vascular vessels. To overcome this obstacle, we employed ZNF580 gene complexed with biodegradable microparticles (MPs) to promote the rapid endothelialization by ECs. In order to realize the controlled release of ZNF580 gene from MPs/gene complexes, a series of amphiphilic triblock copolymers with different degradation rate, namely, methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione)-graft-polyethyleneimine (mPEG-b-PMMD-g-PEI), methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione-co-lactide)-graft-polyethyleneimine (mPEG-b-P(MMD-co-LA)-g-PEI) and methoxy-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione-co-lactide-co-glycolide)-graft-polyethyleneimine (mPEG-b-P(MMD-co-LA-co-GA)-g-PEI), were synthesized. Then, MPs were formed by self-assembly. The hydrophobic cores of these MPs were composed of PMMD, P(MMD-LA) or P(MMD-co-LA-co-GA) segments, and provided crosslinking points for numbers of PEG and short PEI chains to form a high hydrophilic and positive charged corona/shell structure. Based on their positive charged surface, MPs can compact pEGFP-ZNF580 into MPs/pEGFP-ZNF580 complexes. The cell transfection result demonstrated that pEGFP-ZNF580 could be transported efficiently into ECs by these complexes. The result of western blot showed that the relative ZNF580 protein level can increase to 35.74%-46.11% by the overexpression of ZNF580 gene. Furthermore, the release of pEGFP-ZNF580 could be sustained at least 25 days due to the controllable degradation ability of the hydrophobic MPs' core. The MPs and MPs/pEGFP-ZNF580 complexes showed low cytotoxicity because of the introduction of PEG chains and low molecular weight PEI on the surface of these MPs. Notably, at the low concentration (20 µg/mL), the MPs and their complexes were non-cytotoxicity. The rapid endothelialization was promoted significantly by the expression of pEGFP-ZNF580.

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