[Silver Ion Decreases Foreign Body Reaction and Venous Neointimal Hyperplasia through the Inhibition of Interleukin-33 Expression].

INTRODUCTION: Vascular prosthetic grafts are widely used in vascular surgery; however, graft infection remains a major concern. Silver-coated vascular grafts have demonstrated anti-infection properties in clinical settings; however, whether the silver irons influence foreign body reaction or neointimal hyperplasia remains unclear. METHODS: Sodium alginate and hyaluronic acid (SA/HA) hydrogel patches loaded with rhodamine, with or without silver, were fabricated. Patches were implanted in the subcutaneous or abdominal cavity and inferior vena cava of rats. Samples were harvested on day 14 and examined via immunohistochemical and immunofluorescence analyses. RESULTS: Silver hydrogel was found to decrease the foreign body reaction; after subcutaneous and abdominal cavity implantation in rats, the capsule was found to be thinner in the silver hydrogel group than in the control hydrogel group. The silver hydrogel group had fewer CD68-positive cells and proliferating cell nuclear antigen and interleukin-33 (IL-33) dual-positive cells than the control hydrogel group. Additionally, the silver hydrogel patch reduced the neointimal thickness after patch venoplasty in rats, and the number of IL-33- and IL-1ß-positive cells was lower than that in the control patch. CONCLUSION: Silver-loaded SA/HA hydrogel patches decreased the foreign body reaction and venous neointimal hyperplasia in rats by the inhibition of IL-33 expression.

Three-dimensional bioprinting of artificial blood vessel: Process, bioinks, and challenges.

The coronary artery bypass grafting is a main treatment for restoring the blood supply to the ischemic site by bypassing the narrow part, thereby improving the heart function of the patients. Autologous blood vessels are preferred in coronary artery bypass grafting, but their availability is often limited by due to the underlying disease. Thus, tissue-engineered vascular grafts that are devoid of thrombosis and have mechanical properties comparable to those of natural vessels are urgently required for clinical applications. Most of the commercially available artificial implants are made from polymers, which are prone to thrombosis and restenosis. The biomimetic artificial blood vessel containing vascular tissue cells is the most ideal implant material. Due to its precision control ability, three-dimensional (3D) bioprinting is a promising method to prepare biomimetic system. In the 3D bioprinting process, the bioink is at the core state for building the topological structure and keeping the cell viable. Therefore, in this review, the basic properties and viable materials of the bioink are discussed, and the research of natural polymers in bioink, including decellularized extracellular matrix, hyaluronic acid, and collagen, is emphasized. Besides, the advantages of alginate and Pluronic F127, which are the mainstream sacrificial material during the preparation of artificial vascular graft, are also reviewed. Finally, an overview of the applications in the field of artificial blood vessel is also presented.

Deoxygenative Radical Boration of Inert Amides via a Combination of Relay and Cooperative Catalysis.

Invited for the cover of this issue is the group of Prof. Xiaoming Wang at the Shanghai Institute of Organic Chemistry and Hangzhou Institute for Advanced Study, University of the Chinese Academy of Sciences. The image depicts a combination of relay and cooperative catalysis with a triple iridium-photoredox-organocatalysis system to achieve an unprecedented reductive boration of amides. Read the full text of the article at 10.1002/chem.202301199.

Deoxygenative Radical Boration of Inert Amides via a Combination of Relay and Cooperative Catalysis.

One of the most challenging tasks in organic synthesis is to develop novel methodologies for rapid construction of complex molecules starting from easily available yet inert raw materials. In this context, multi-catalysis strategies have attracted great attention in the discovery of new reactivity profiles that may allow access to many difficult or unattainable transformations. So far the deoxygenative functionalization of ubiquitous amides is usually achieved by nucleophilic attack on the imine or iminium ion intermediate formed via activation of the C=O bond, and these functionalization reagents were often confined to C-based nucleophiles, which largely limited the diversity of the resultant amines. Herein, we disclose a combined strategy of relay and cooperative catalysis with a triple iridium-photoredox-organocatalysis system to achieve an unprecedented reductive boration of amides, affording valuable α-amino boron products which are viable building blocks. In this transformation, the Ir-catalyzed semi-reduction of amides is successfully incorporated with photo-organic catalyzed nucleophilic boryl radical addition, thus delivering the corresponding α-boryl amines in high efficiency.

Wood-Derived Vascular Patches Loaded With Rapamycin Inhibit Neointimal Hyperplasia.

Background: Patches are commonly used to close blood vessels after vascular surgery. Most currently used materials are either prosthetics or animal-derived; although natural materials, such as a leaf, can be used as a patch, healing of these natural materials is not optimal; rhodamine and rapamycin have been used to show that coating patches with drugs allow drug delivery to inhibit neointimal hyperplasia that may improve patch healing. Wood is abundant, and its stiffness can be reduced with processing; however, whether wood can be used as a vascular patch is not established. We hypothesized that wood can be used as a vascular patch and thus may serve as a novel plant-based biocompatible material. Method: Male Sprague-Dawley rats (aged 6-8 weeks) were used as an inferior vena cava (IVC) patch venoplasty model. After softening, wood patches coated with rhodamine and rapamycin were implanted into the rat subcutaneous tissue, the abdominal cavity, or the IVC. Samples were explanted on day 14 for analysis. Result: Wood patches became soft after processing. Patches showed biocompatibility after implantation into the subcutaneous tissue or the abdominal cavity. After implantation into the IVC, the patches retained mechanical strength. There was a significantly thinner neointima in wood patches coated with rapamycin than control patches (146.7 ± 15.32 µm vs. 524.7 ± 26.81 µm; p = 0.0001). There were CD34 and nestin-positive cells throughout the patch, and neointimal endothelial cells were Eph-B4 and COUP-TFII-positive. There was a significantly smaller number of PCNA and α-actin dual-positive cells in the neointima (p = 0.0003), peri-patch area (p = 0.0198), and adventitia (p = 0.0004) in wood patches coated with rapamycin than control patches. Piezo1 was expressed in the neointima and peri-patch area, and there were decreased CD68 and piezo1 dual-positive cells in wood patches coated with rapamycin compared to control patches. Conclusion: Wood can be used as a novel biomaterial that can be implanted as a vascular patch and also serve as a scaffold for drug delivery. Plant-derived materials may be an alternative to prosthetics or animal-based materials in vascular applications.

ADAM17: A novel treatment target for aneurysms.

PURPOSE: The mechanisms underlying abdominal aortic aneurysms (AAAs) are still not fully understood, previous researches showed ADAM17 is increased in aneurysm. We hypothesized that inhibiting ADAM17 can decrease AAA formation and progression. MATERIALS AND METHODS: Aneurysm models were established in mouses and rats by aortic adventitial CaCl2 incubation and aortic pericardial patch angioplasty respectively. In mouse, control (no treatment) or SA/HA hydrogel loaded with TAPI-1 (ADAM17 inhibitor) were adventitial applied; in rat, control and TAPI-1 coated pericardial patch were used in rat aortic pericardial patch angioplasty. Samples were harvested on day 14 or 30 and analyzed by immunofluorescence. Bioinformatics analysis and immunostaining analysis were carried out to confirm the therapeutic potential of ADAM17 in the human AAA. RESULTS: ADAM17 was highly expressed in mouses, rats and human aneurysms. Adventitial application of SA/HA hydrogel loaded TAPI-1 or TAPI-1 conjugated pericardial patch can decrease AAA formation and progression in mouses and rats, respectively. Bioinformatic analysis showed ADAM17 promotes transformation of M1 macrophages and synthetic vascular smooth muscle cells, together with immunostaining analysis and results from animal models, the therapeutic potential of ADAM17 in the human AAA were confirmed. CONCLUSION: We showed that local delivery of ADAM17 inhibitor can inhibit aneurysm formation and progression in mouse and rat, these results showed ADAM17 plays an important role in the aneurysm formation and may be a potential treatment target.

The application of tissue-engineered fish swim bladder vascular graft.

Small diameter (< 6 mm) prosthetic vascular grafts continue to show very low long-term patency, but bioengineered vascular grafts show promising results in preclinical experiments. To assess a new scaffold source, we tested the use of decellularized fish swim bladder as a vascular patch and tube in rats. Fresh goldfish (Carassius auratus) swim bladder was decellularized, coated with rapamycin and then formed into patches or tubes for implantation in vivo. The rapamycin-coated patches showed decreased neointimal thickness in both the aorta and inferior vena cava patch angioplasty models. Rapamycin-coated decellularized swim bladder tubes implanted into the aorta showed decreased neointimal thickness compared to uncoated tubes, as well as fewer macrophages. These data show that the fish swim bladder can be used as a scaffold source for tissue-engineering vascular patches or vessels.

Hydrogel-coated needles prevent puncture site bleeding in arteriovenous fistula and arteriovenous grafts in rats.

INTRODUCTION: Imperfect hemostasis after arteriovenous fistula (AVF) and arteriovenous graft (AVG) cannulation can cause a hematoma or pseudoaneurysm and leads to poor satisfaction. We hypothesized that a hydrogel-coated needle would effectively and rapidly stop bleeding after vascular cannulation in a rat AVF and AVG model. METHOD: A hydrogel comprised of sodium alginate (SA), hyaluronic acid (HA), and calcium carbonate was coated onto the surface of suture needles using a rotating system. The needles were observed using scanning electron microscopy (SEM) and immunofluorescence. Rat AVF with or without renal failure and AVG were punctured using bare and hydrogel-coated needles. The tissues were examined by histology. RESULT: The hydrogel was successfully coated onto the surface of 30 G needles and confirmed by SEM. Hydrogel-coated needles rapidly stopped bleeding after AVF and AVG cannulation in rat. CONCLUSION: In this preliminary animal research, hydrogel-coated needles can stop AVF and AVG puncture-site bleeding; but additional clinical studies are needed to justify whether it is still effective in clinical.

Advances in coatings on magnesium alloys for cardiovascular stents - A review.

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.

Programmed death-1 mediates venous neointimal hyperplasia in humans and rats.

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.

A novel intramural TGF ß 1 hydrogel delivery method to decrease murine abdominal aortic aneurysm and rat aortic pseudoaneurysm formation and progression.

OBJECTIVES: Aneurysms are generally the result of dilation of all 3 layers of the vessel wall, and pseudoaneurysms are the result of localized extravasation of blood that is contained by surrounding tissue. Since there is still no recommended protocol to decrease aneurysm formation and progression, we hypothesised that intramural delivery of TGF ß1 hydrogel can decrease aneurysm and pseudoaneurysm formation and progression. MATERIALS: Male C57BL/6 J mice (12-14 wk), SD rats (200 g) and pig abdominal aortas were used, and hydrogels were fabricated by the interaction of sodium alginate (SA), hyaluronic acid (HA) and CaCO3. METHODS: A CaCl2 adventitial incubation model in mice and a decellularized human great saphenous vein patch angioplasty model in rats were used. TGF ß1 hydrogel was intramurally delivered after CaCl2 incubation in mice; at day 7, the abdomen in some mice was reopened, and TGF ß1 hydrogel was injected intramurally into the aorta. In rats, TGF ß1 hydrogel was delivered intramurally after patch angioplasty completion. Tissues were harvested at day 14 and analysed by histology and immunohistochemistry staining. The pig aorta was also intramurally injected with hydrogel. RESULTS: In mice, rhodamine hydrogel was still found between the medium and adventitia at day 14. In the mouse aneurysm model, there was a thicker wall and smaller amount of elastin breaks in the TGF ß1 hydrogel-delivered groups both at day 0 and day 7 after CaCl2 incubation, and there were larger numbers of p-smad2- and TAK1-positive cells in the TGF ß1 hydrogel-injected groups. In the rat decellularized human saphenous vein patch pseudoaneurysm model, there was a higher incidence of pseudoaneurysm formation when the patch was decellularized using 3% SDS, and delivery of TGF ß1 hydrogel could effectively decrease the formation of pseudoaneurysm formation and increase p-smad2 and TAK1 expression. In pig aortas, hydrogels can be delivered between the medium and adventitia easily and successfully. CONCLUSIONS: Intramural delivery of TGF ß1 hydrogel can effectively decease aneurysm and pseudoaneurysm formation and progression in both mice and rats, and pig aortas can also be successfully intramurally injected with hydrogel. This technique may be a promising drug delivery method and therapeutic choice to decrease aneurysm and pseudoaneurysm formation and progression in the clinic.

Enhancing biocompatibility and corrosion resistance of biodegradable Mg-Zn-Y-Nd alloy by preparing PDA/HA coating for potential application of cardiovascular biomaterials.

In this paper the poly-dopamine (PDA)/hyaluronic acid (HA) coatings with different HA molecular weight (MW, 4 × 103, 1 × 105, 5 × 105 and 1 × 106 Da) were prepared onto the NaOH passivated Mg-Zn-Y-Nd alloy aiming at potential application of cardiovascular implants. The characterization of weight loss, polarization curves and surface morphology indicated that the coatings with HA MW of 1 × 105 (PDA/HA-2) and 1 × 106 Da (PDA/HA-4) significantly enhanced the corrosion resistance of Mg-Zn-Y-Nd. In vitro biological test also suggested better hemocompatibility, pro-endothelialization, anti-hyperplasia and anti-inflammation functions of the PDA/HA-2- and PDA/HA-4-coated Mg-Zn-Y-Nd alloy. Nevertheless, the in vivo implantation of SD rats' celiac artery demonstrated that the PDA/HA-2 had preferable corrosion resistance and biocompatibility.

An Injectable Nanocomposite Hydrogel for Potential Application of Vascularization and Tissue Repair.

In this contribution, an injectable hydrogel was developed with chitosan, gelatin, ß-glycerphosphate and Arg-Gly-Asp (RGD) peptide: this hydrogel is liquid in room temperature and rapidly gels at 37 °C; RGD peptide promises better growth microenvironment for various cells, especially endothelial cells (EC), smooth muscle cells (SMC) and mesenchymal stem cells (MSC). Both stromal cell-derived factor-1 (SDF-1) nanoparticle and vascular endothelial growth factor (VEGF) nanoparticles were loaded in the injectable hydrogel to simulate the natural nanoparticles in the extracellular matrix (ECM) to promote angiogenesis. In vitro EC/SMC and MSC/SMC co-culture experiment indicated that the nanocomposite hydrogel accelerated constructing embryonic form of blood vessels, and chick embryo chorioallantoic membrane model demonstrated its ability of improving cells migration and blood vessel regeneration. We injected this nanocomposite hydrogel into rat myocardial infarction (MI) model and the results indicated that the rats heart function recovered better compared control group. We hope this injectable nanocomposite hydrogel may possess wider application in tissue engineering.

Tailoring of cardiovascular stent material surface by immobilizing exosomes for better pro-endothelialization function.

Stent intervention as available method in clinic has been widely applied for cardiovascular disease treatment for decades. However, the restenosis caused by late thrombosis and hyperplasia still limits the stents long-term application, and the essential cause is usually recognized as endothelial functionalization insufficiency of the stent material surface. Here, we address this limitation by developing a pro-endothelial-functionalization surface that immobilized a natural factors-loaded nanoparticle, exosome, onto the poly-dopamine (PDA) coated materials via electrostatic binding. This PDA/Exosome surface not only increased the endothelial cells number on the materials, but also improved their endothelial function, including platelet endothelial cell adhesion molecule-1 (CD31) expression, cell migration and nitric oxide release. The pro-inflammation macrophage (M1 phenotype) attachment and synthetic smooth muscle cell proliferation as the interference factors for the endothelialization were not only inhibited by the PDA/Exosome coating, while the cells were also regulated to anti-inflammation macrophage (M2 phenotype) and contractile smooth muscle cell, which may contribute to endothelialization. Thus, it can be summarized this method has potential application on surface modification of cardiovascular biomaterials.

Effects of degradation products of biomedical magnesium alloys on nitric oxide release from vascular endothelial cells.

Nitric oxide (NO) released by vascular endothelial cells (VECs), as a functional factor and signal pathway molecule, plays an important role in regulating vasodilation, inhibiting thrombosis, proliferation and inflammation. Therefore, numerous researches have reported the relationship between the NO level in VECs and the cardiovascular biomaterials' structure/functions. In recent years, biomedical magnesium (Mg) alloys have been widely studied and rapidly developed in the cardiovascular stent field for their biodegradable absorption property. However, influence of the Mg alloys' degradation products on VEC NO release is still unclear. In this work, Mg-Zn-Y-Nd, an Mg alloy widely applied on the biodegradable stent research, was investigated on the influence of the degradation time, the concentration and reaction time of degradation products on VEC NO release. The data showed that the degradation product concentration and the reaction time of degradation products had positive correlation with NO release, and the degradation time had negative correlation with NO release. All these influencing factors were controlled by the Mg alloy degradation behaviors. It was anticipated that it might make sense for the cardiovascular Mg alloy design aiming at VEC NO release and therapy.

An injectable scaffold based on temperature-responsive hydrogel and factor-loaded nanoparticles for application in vascularization in tissue engineering.

Controlled release of functional factors contributes to target migration of therapeutic cells and plays a crucial role in the in situ vascularization of tissue repair and regeneration. A biomedical application requires the selective release of multiple factors which will guide the synergy of the cells. Here, we developed an injectable system based on a temperature-responsive hydrogel and stromal cell-derived factor-1 (SDF-1)/vascular endothelial growth factor (VEGF) loaded into two types of nanoparticles to induce migration and rapid proliferation of mesenchymal stem cells (MSCs) and endothelial cells (ECs) via selective SDF-1/VEGF release. Series of in vitro and in vivo experiments demonstrate that our composited system can accurately guide MSCs and ECs for vascularization. In addition, the properties of the nanoparticles and hydrogel, including micro/nanoscales, characteristic of charge, and biocompatibility, played crucial roles for the selective release and cells behavior (target migration and rapid proliferation).

Preparation of a biomimetic ECM surface on cardiovascular biomaterials via a novel layer-by-layer decellularization for better biocompatibility.

Endothelial extracellular matrix (EC-ECM) modification by decellularization is generally recognized as an effective method for cardiovascular biomaterials to enhance their biocompatibility. However, the now available EC-ECM was mainly secreted by the in vitro cultured endothelial cells which lacked a physiological growth environment in vivo, such as blood flow shear stress (BFSS) acting, thus had a serious defect of biocompatibility. Our previous work markedly improved the biocompatibility of the EC-ECM modified materials by simulating the BFSS acting to control the endothelial cells with hyaluronic acid (HA) micro-pattern. In this contribution, the EC-ECM was further enriched onto the HA micro-pattern via a novel layer-by-layer decellularizatio method. In vitro platelets adhesion/activation, macrophages attachment test and ex vivo blood experiment of New Zealand White Rabbits suggested better blood compatibility and anti-inflammation property of this novel biomimetic ECM surface. The endothelial cells culture tests and in vivo rat subcutaneous implantation also proved its good pro-endothelialization function and tissue compatibility. In summary, the present study demonstrated better biocompatibility of the novel biomimetic ECM surface and its potential application for cardiovascular biomaterials modification.

Mechanical Property of TiO2 Nano-Tubes Surface Based on the Investigation of Residual Stress, Tensile Force and Fluid Flow Shear Stress: For Potential Application of Cardiovascular Devices.

The TiO2 nanotube has been anticipated for potential application for cardiovascular implanted devices for its excellent drug loading/release function and biocompatibility. However, its mechanical behavior has rarely been studied as the cardiovascular devices. The tube length is a crucial factor which not only decides the drug loading ability but also influences the devices' mechanical behavior. Therefore, in this work, the TiO2 nanotubes with different tube length (NT2, NT4 and NT6) were fabricated, and their surface energy, residual stress, tensile tolerability and blood flow shear stress tolerability were determined, respectively. The results showed that there were no significant difference for each film samples on surface energy, tensile tolerability and blood flow shear stress tolerability, while NT6 obtained the smallest residual stress. These results indicated that longer TiO2 nanotubes not only meant loading more drugs but also better mechanical properties for surface modification of cardiovascular devices.

Platelet Adhesion and Activation on Chiral Surfaces: The Influence of Protein Adsorption.

Adsorbed proteins and their conformational change on blood-contacting biomaterials will determine their final hemocompatibility. It has frequently been reported that surface chirality of biomaterials may highly influence their protein adsorption behavior. Here, lysine and tartaric acid with different chirality were immobilized onto TiO2 films respectively, and the influence of surface chirality on protein adsorption, platelet adhesion, and activation was also investigated. It showed that the l- and d-molecule grafted samples had almost the same grafting density, surface topography, chemical components, and hydrophilicity in this study. However, biological behaviors such as protein adsorption, platelet adhesion, and activation were quite different. The d-lysine grafted surface had a greater ability to inhibit both bovine serum albumin and fibrinogen adsorption, along with less degeneration of fibrinogen compared to the l-lysine anchored surface. However, the d-tartaric acid grafted surface adsorbed more protein but with less denatured fibrinogen compared to the l-tartaric acid grafted one. Further studies showed that the secondary structural change of the adsorbed albumin and fibrinogen on all surfaces with deduction of the α-helix content and increase of disordered structure, while the changing degree was apparently varied. As a result, the d-lysine immobilized surface absorbed less platelets and red blood cells and achieved slightly increased platelet activation. For tartaric acid anchored surfaces, a larger number of platelets adhered to the D-surface but were less activated compared to the L-surface. In conclusion, the surface chirality significantly influenced the adsorption and conformational change of blood plasma protein, which in turn influenced both platelet adhesion and activation.

Constructing bio-layer of heparin and type IV collagen on titanium surface for improving its endothelialization and blood compatibility.

The modification of cardiovascular stent surface for a better micro-environment has gradually changed to multi-molecule, multi-functional designation. In this study, heparin (Hep) and type IV collagen (IVCol) were used as the functional molecule to construct a bifunctional micro-environment of anticoagulation and promoting endothelialization on titanium (Ti). The surface characterization results (AFM, Alcian Blue 8GX Staining and fluorescence staining of IVCol) indicated that the bio-layer of Hep and IVCol were successfully fabricated on the Ti surface through electrostatic self-assembly. The APTT and platelet adhesion test demonstrated that the bionic layer possessed better blood compatibility compared with Ti surface. The adhesion, proliferation, migration and apoptosis tests of endothelial cells proved that the Hep/IVCol layer was able to enhance the endothelialization of the Ti surface. The in vivo animal implantation results manifested that the bionic surface could encourage new endothelialization. This work provides an important reference for the construction of multifunction micro-environment on the cardiovascular scaffold surface.