Hemocompatibility Multi-in-One Hydrogel Coating with ROS-Triggered Inflammation Suppression and Anti-Infection Properties for Blood-Contacting Device.

In traditional blood-contacting medical devices, infection and thrombosis are easily formed on the surface of the materials. In addition, inflammation is also a clinical complication that cannot be ignored. More importantly, there is a mutually promoting relationship between the inflammatory response and the infection as well as thrombosis. In this work, we propose a self-adaptive anti-inflammatory coating strategy combined with anti-infection and anticoagulant capacity, which was accomplished based on nano-Ag particles and dexamethasone (Dex)-loaded hydrogel coating. The coating loaded with nano-Ag endows it with good bactericidal performance, including Gram-positive and Gram-negative bacteria. As an anti-inflammatory drug, Dex was grafted onto hydrogel coating by a reactive oxygen species (ROS)-cleavable thioketal (TK) bond and released upon the trigger of an inflammatory environment, blocking further inflammatory cascade, providing self-adaptive anti-inflammatory properties, and avoiding side effects of the drug. It was demonstrated that the coating worked as a precise strategy to resist coagulation, infection, and inflammation, provided a new perspective for designing clinical complication-conformable coatings, and had great application prospects on blood-contacting medical 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.

Passivation protein-adhesion platform promoting stent reendothelialization using two-electron-assisted oxidation of polyphenols.

Superhydrophilic surfaces play an important role in nature. Inspired by this, scientists have designed various superhydrophilic materials that are widely used in the field of biomaterials, such as PEG molecular brushes and zwitterionic materials. However, superhydrophilic coatings with only anti-fouling properties do not satisfy the requirements for rapid reendothelialization of cardiovascular stent surfaces. Herein, a novel polyphenol superhydrophilic surface with passivated protein-adsorption properties was developed using two-electron oxidation of dopamine and polyphenols. This coating has a multiscale effects: 1) macroscopically: anti-fouling properties of superhydrophilic; 2) microscopically: protein adhesion properties of active groups (quinone-, amino-, hydroxyphenyl groups and aromatic ring). Polyphenols not only enhance the ability of coating to passivate protein-adsorption, but also make the coating have polyphenol-related biological functions. Therefore, the polyphenol and passivated protein-adsorption platform together maintain the stability of the scaffold microenvironment. This, in turn, provides favorable conditions for the growth of endothelial cells on the scaffold surface. In vivo implantation of the coated stents into the abdominal aorta resulted in uniform and dense endothelial cells covering the surface of the neointima. Moreover, new endothelial cells secreted large amounts of functional endothelial nitric oxide synthase like healthy endothelial cells. These results indicate that the polyphenol superhydrophilic coating potentially resists intra-stent restenosis and promotes surface reendothelialization. Hence, polyphenol superhydrophilic coatings with passivated protein-adsorption properties constructed by two-electron-assisted oxidation are a highly effective and versatile surface-modification strategy for implantable cardiovascular devices.

Polymer Complex Multilayers for Drug Delivery and Medical Devices.

Polymer complex multilayers (PCMs) can be engineered into various structures with tunable properties via layer-by-layer (LBL) assembly driven by noncovalent forces. Due to their ease of preparation, capability of integrating multiple functional components, and excellent substrate compliance, biocompatible PCMs as coating materials or individual entities have attracted extensive attention in biomedical applications. This Spotlight on Applications presents recent progress on PCMs applied for drug delivery and medical devices. We provide several examples to address the importance of using PCM platforms to achieve controlled drug delivery including stimuli-triggered release, sustained release, and spatiotemporal sequential release. The effects of PCM coatings on the bioresponse regulation and performance enhancement of implantable devices are also highlighted. Moreover, the design and fabrication of flexible electrical and optical elements modified with LBL PCMs have been discussed, which demonstrates the great potential to advance emerging wearable devices for disease monitoring and health management.

Development of Innovative Biomaterials and Devices for the Treatment of Cardiovascular Diseases.

Cardiovascular diseases have become the leading cause of death worldwide. The increasing burden of cardiovascular diseases has become a major public health problem and how to carry out efficient and reliable treatment of cardiovascular diseases has become an urgent global problem to be solved. Recently, implantable biomaterials and devices, especially minimally invasive interventional ones, such as vascular stents, artificial heart valves, bioprosthetic cardiac occluders, artificial graft cardiac patches, atrial shunts, and injectable hydrogels against heart failure, have become the most effective means in the treatment of cardiovascular diseases. Herein, an overview of the challenges and research frontier of innovative biomaterials and devices for the treatment of cardiovascular diseases is provided, and their future development directions are discussed.

A multi-in-one strategy with glucose-triggered long-term antithrombogenicity and sequentially enhanced endothelialization for biological valve leaflets.

Bioprosthetic heart valves are commonly applied in heart valve replacement, while the effectiveness is limited by inflammation, calcification and especially thrombosis. Surface modification is expected to endow the biological valves with versatility. Herein, a multi-in-one strategy was established to modify biological valves with long-term antithrombogenicity and sequentially enhanced endothelialization triggered by glucose, in which the direct thrombin inhibitor rivaroxaban (RIVA)-loaded nanogels were embedded and the detachable polyethylene glycol (PEG) was grafted. These two anticoagulant strategies were connected by glucose oxidase (GOx), which catalyzed the oxidation of glucose to produce hydrogen peroxide (H2O2) and local acidic environment. The generated H2O2 stimulated H2O2-responsive nanogels release RIVA to obtain continuous antithrombogenicity. Meanwhile, PEG was attached to the surface via pH-sensitive bonds, which prevented thrombus formation by resisting the serum proteins and platelets adhesion at the initial stage of material/blood contact. Sequentially, PEG gradually peeled off under the local weak acidic environment, which ultimately resulted in the endothelialization enhancement. Within such multi-in-one strategy, the biological valve leaflets induced long-term anticoagulant performance, gradually enhanced endothelialization and improved tissue affinity, including anti-calcification and anti-inflammation, indicating the potential of the response sequence matching between materials and tissues after implantation, which might improve performance of biological heart valves.

Dressing Blood-Contacting Materials by a Stable Hydrogel Coating with Embedded Antimicrobial Peptides for Robust Antibacterial and Antithrombus Properties.

Although dressing blood-contacting devices with robust and synergistic antibacterial and antithrombus properties has been explored for several decades, it still remains a great challenge. In order to endow materials with remarkable antibacterial and antithrombus abilities, a stable and antifouling hydrogel coating was developed via surface-initiated polymerization of sulfobetaine methacrylate and acrylic acid on a polymeric substrate followed by embedding of antimicrobial peptides (AMPs), including WR (sequence: WRWRWR-NH2) or Bac2A (sequence: RLARIVVIRVAR-NH2) AMPs. The chemical composition of the AMP-embedded hydrogel coating was determined through XPS, zeta potential, and SEM-EDS measurements. The AMP-embedded antifouling hydrogel coating showed not only good hemocompatibility but also excellent bactericidal and antiadhesion properties against Gram-positive and Gram-negative bacteria. Moreover, the hydrogel coating could protect the AMPs with long-term bioactivity and cover the positive charge of the dotted distributed AMPs, which in turn well retained the hemocompatibility and antifouling capacity of the bulk hydrogels. Furthermore, the microbiological results of animal experiments also verified the anti-infection performance in vivo. Histological and immunological data further indicated that the hydrogel coating had an excellent anti-inflammatory function. Therefore, the present study might provide a promising approach to prevent bacterial infections and thrombosis in clinical applications of blood-contacting devices and related implants.

Epigallocatechin gallate mediated sandwich-like coating for mimicking endothelium with sustained therapeutic nitric oxide generation and heparin release.

In-stent restenosis after stenting is generally characterized by an inflammatory response, excessive proliferation of smooth muscle cells, and delayed healing of the endothelium layer. In this study, inspired by catechol/gallol surface chemistry, a sandwich-like layer-by-layer (LBL) coating was developed using chitosan and heparin as polyelectrolytes, along with the embedding of an epigallocatechin gallate/copper (EGCG/Cu) complex. The embedding of EGCG stabilized the coating by various intermolecular interactions in the LBL coating (e.g., π-π stacking, weak intermolecular crosslinking, and enriched hydrogen bonding) and supported the sustained release of the cargo heparin over 90 days. This design enabled a biomimetic endothelium function in terms of the sustained release of heparin and continuous in situ generation of nitric oxide, driven by the catalytic decomposition of endogenous S-nitrostothiols by copper ions. The result showed enhanced durability of anticoagulation and suppressed inflammatory response. Moreover, the "sandwich-like" coating supported the growth of endothelial cells and up-regulated the protein expression of vascular endothelial growth factor, while effectively suppressing the proliferation and migration of smooth muscle cells (SMCs) via the up-regulation of cyclic guanosine monophosphate. Ex vivo and in vivo experiments demonstrated the effectiveness of the sandwich-like coating in preventing thrombosis formation, suppressing the growth of SMCs, reducing the infiltration and activation of inflammatory cells, and ultimately achieving rapid in situ endothelialization. Hence, the EGCG-assisted sandwich-like coating might be used as a robust and versatile surface modification strategy for implantable cardiovascular devices.

A honokiol-mediated robust coating for blood-contacting devices with anti-inflammatory, antibacterial and antithrombotic properties.

Thrombus, bacterial infections, and severe inflammation are still serious problems that have to be faced with blood-contacting materials. However, it is a great challenge to simultaneously meet the above functional requirements in a simple, economical and efficient method. As such, we put forward a robust and versatile coating strategy by covalently modifying the multi-pharmacological drug honokiol (HK) with an amine-rich polydopamine/polyethyleneimine coating, through which anticoagulant, antibacterial and anti-inflammatory properties were obtained (DPHc) simultaneously. The amine content in the DPHc coating was lower than the detection limit, while it contained abundant phenolic hydroxyl groups (49 µmol cm-2). Meanwhile, the 30 day drug release test confirmed that the drug was firmly modified on the surface of the coating without release. A systematic in vitro and ex vivo evaluation confirmed that the coating had significant anti-thrombotic properties. The antibacterial rates of the DPHc coating against Staphylococcus aureus and Escherichia coli reached 99.98% and 99.99%, respectively. In addition, subcutaneous implantation indicated that the DPHc coating also has excellent histocompatibility. To the best of our knowledge, this is the first study using HK as a coating material that can not only combat thrombosis and infection but also significantly inhibit inflammation associated with the use of blood-contacting materials, thus expanding the application of HK in the field of biomaterials.

A tailored extracellular matrix (ECM) - Mimetic coating for cardiovascular stents by stepwise assembly of hyaluronic acid and recombinant human type III collagen.

Collagen, a central component of the extracellular matrix (ECM), has been widely applied in tissue engineering, among others, for wound healing or bone and nerve regeneration. However, the inherent thrombogenic properties of collagen hinder the application in blood-contacting devices. Herein, a brand-new recombinant human type III collagen (hCOLIII) was explored that does not present binding sites for platelets while retaining the affinity for endothelial cells. The hCOLIII together with hyaluronic acid (HA) were deposited on the substrates via layer-by-layer assembly to form an ECM-mimetic multilayer coating. In vitro platelet adhesion and ex vivo blood circulation tests demonstrated prominent thromboprotective properties for the hCOLIII-based ECM-mimetic coating. In addition, the coating effectively guided the vascular cell fate by supporting the proliferation of endothelial cells and inhibiting the proliferation of smooth muscle cells by differentiating them to a more contractile phenotype. A polylactic acid (PLA) stent coated with hCOLIII-based ECM-mimetic coating was implanted in the abdominal aorta of rabbits to investigate the healing of the neointima. The enhanced endothelialization, suppressed inflammatory response, inhibition of excessive neointimal hyperplasia, and the superior thromboprotection strongly indicated the prospect of the hCOLIII-based ECM-mimetic coating as a tailored blood-contacting material for cardiovascular stents.

A conformally adapted all-in-one hydrogel coating: towards robust hemocompatibility and bactericidal activity.

Hospital-acquired infections and thrombosis caused by bacteria attached to the device surface, or fibrin crosslinking owing to platelet accumulation/activation, are major healthcare challenges that cause morbidity and mortality. To prevent these, surface coating technologies are considered an efficient tool that can combine hemocompatibility and bactericidal activity. In this study, surface-initiated polymerization was conducted to form an all-in-one hydrogel coating that could adapt to diverse medical devices. Different monomer ratios (acrylamide/acrylic acid) were used to adjust the antimicrobial agent loading capacity. The hydrogel coating obtained by a simple dip-absorbing method showed good hemocompatibility and maintained efficient bactericidal activity. We also explored the loading and release of antimicrobial agents with different molecular sizes, including nano-Ag particles, antibiotics, and antimicrobial peptides. The inhibition zone test and confocal laser scanning microscopy revealed that the hydrogel coating could maintain remarkable antimicrobial and antifouling properties for four weeks. Furthermore, the hydrogel coating decreased the platelet adhesion/activation without risk of hemolysis. The ex vivo blood circulation study confirmed the antithrombotic properties of the hydrogel coating. Such all-in-one hydrogel coatings that maintain high cell viability and exhibit both hemocompatibility and bactericidal activity possess the potential for applications in blood-contacting devices.

Heart Valves Cross-Linked with Erythrocyte Membrane Drug-Loaded Nanoparticles as a Biomimetic Strategy for Anti-coagulation, Anti-inflammation, Anti-calcification, and Endothelialization.

In recent years, valvular heart disease has become a serious disease threatening human life and is a major cause of death worldwide. However, the glutaraldehyde (GLU)-treated biological heart valves (BHVs) fail to meet all requirements of clinical application due to disadvantages such as valve thrombus, cytotoxicity, endothelialization difficulty, immune response, and calcification. Encouragingly, there are a large number of carboxyls as well as a few amino groups on the surface of GLU-treated BHVs that can be modified to enhance biocompatibility. Inspired by natural biological systems, we report a novel approach in which the heart valve was cross-linked with erythrocyte membrane biomimetic drug-loaded nanoparticles. Such modified heart valves not only preserved the structural integrity, stability, and mechanical properties of the GLU-treated BHVs but also greatly improved anti-coagulation, anti-inflammation, anti-calcification, and endothelialization. The in vitro results demonstrated that the modified heart valves had long-term anti-coagulation properties and enhanced endothelialization processes. The modified heart valves also showed good biocompatibility, including blood and cell biocompatibility. Most importantly, the modified heart valves reduced the TNF-α levels and increased IL-10 compared to GLU-treated BHVs. In vivo animal experiments also confirmed that the modified heart valves had an ultrastrong resistance to calcification after implantation in rats for 120 days. The mechanism of anti-calcification in vivo was mainly due to the controlled release of anti-inflammatory drugs that reduced the inflammatory response after valve implantation. In summary, this therapeutic approach based on BHVs cross-linking with erythrocyte membrane biomimetic nanoparticles sparks a novel design for valvular heart disease therapy.

Phosphorylcholine- and cation-bearing copolymer coating with superior antibiofilm and antithrombotic properties for blood-contacting devices.

Nosocomial infections resulting from bacterial attachment on blood-contacting medical devices, as well as biofilm and thrombus formation caused by fibrin crosslinking and platelet accumulation/activation are a major health concern and may lead to severe morbidity and mortality. Therefore, there is an urgent need to develop facile and efficient surface coatings with both antibiofilm and antithrombotic properties to prevent medical-device associated infections as well as thrombus formation. In this study, the copolymers containing quaternary ammonium (QA) and phosphorylcholine (PC) groups were synthesized through traditional free-radical copolymerization. The cationic group of QA provides bactericidal properties, and the cell membrane-mimicking group of PC provides antithrombotic and antifouling properties. Long-term stability of the copolymer coating was achieved via simple dip coating. X-ray photoelectron spectroscopy and water contact angle measurement demonstrated that the QA and PC groups possessed inversion properties once in contact with water allowing for long-term stability. Scanning electron microscopy and confocal laser scanning microscopy demonstrated that the copolymer coating could maintain antibiofilm properties for one week in a nutrient-rich environment. Furthermore, the copolymer coating significantly decreased platelet adhesion/activation and did not cause hemolysis. The ex vivo blood circulation showed no thrombus formation which confirmed the excellent antithrombotic property of the copolymer coating. Such coatings that maintain high cell viability and exhibit both antibiofilm and antithrombotic properties present potential applications for blood-contacting devices.

Catechol-mediated and copper-incorporated multilayer coating: An endothelium-mimetic approach for blood-contacting devices.

Implantation of blood-contacting materials/devices usually causes severe thrombus formation, inflammatory reactions, excessive hyperplasia, and ultimately, induce endothelial dysfunction. In this work, a biomimetic approach was established to address those adverse problems through constructing a catechol-mediated and copper-incorporated multilayer coating. The biomimetics was mainly obtained via two paths. The first one was structure bionics, which used polyelectrolytes (heparin and polyethyleneimine) to modify with catechol moieties and then further formed a multilayer coating via layer-by-layer assembly, so as to mimic the mussel adhesive DOPA-rich structure; the second one was function bionics, which copper ions were then incorporated to function as the catalysts to decompose the endogenous S-nitrosothiols to release nitric oxide (NO), so as to mimic the key function of healthy endothelial cells. The quartz crystal microbalance with dissipation (QCM-D) was used to monitor the multilayer construction process and demonstrated the enhanced stability of the catechol-mediated multilayer coatings. Besides, the catechol-rich coating could also support the sustained release of heparin. Copper ions were incorporated into the multilayer coatings via the catechol-Cu coordination, and could effectively generate NO in situ at a physiological level. Due to the sustained release of heparin and continuous NO generation, the synergistic antithrombogenicity and anti-hyperplasia ability were obtained. The ex-vivo arteriovenous (AV) shunt model for blood perfusion test and metal wire implantation in blood vessels further demonstrated the high biomimetic functionality of potential applications for blood-contacting devices.

Polycaprolactone vascular graft with epigallocatechin gallate embedded sandwiched layer-by-layer functionalization for enhanced antithrombogenicity and anti-inflammation.

Small-diameter artificial vascular grafts modified with layer-by-layer (LBL) coating show promise in reducing the failure caused by thrombosis and inflammation, but undesirable stability and bioactivity issues of the coating and payload usually limits their long-term efficacy. Herein, inspired by catechol/gallol surface chemistry, a sandwiched layer-by-layer coating constructed by polyethyleneimine (PEI) and heparin with the embedding of epigallocatechin gallate (EGCG)-dexamethasone combination was used to modify the electrospun polycaprolactone (PCL) vascular grafts. Polyphenol embedding endowed the coating with abundant intermolecular interactions between each coating components, mainly contributed by the π-π stacking, weak intermolecular cross-linking and enriched hydrogen bonding, which further enhanced the coating stability and also supported the sustained release of the payloads, like polyelectrolytes and drugs. Compared with the conventional LBL coating, the loading amounts of heparin and dexamethasone in the EGCG embedded LBL coatings doubled and the drug release could be significantly prolonged without serious initial burst. The in vitro and ex vivo assays indicated that the modified PCL vascular grafts would address impressive prolonged anti-platelet adhesion/activation and anti-fibrinogen denaturation ability. Meanwhile, the dexamethasone loading entrusted the sandwiched LBL coating with mild tissue response, in terms of inhibiting the macrophage activation. These results strongly demonstrated that the sandwiched LBL coating with EGCG embedding was an effective method to improve the patency rates of PCL small artificial vascular grafts, which could also be extended to other blood-contacting materials.

Peptide-/Drug-Directed Self-Assembly of Hybrid Polyurethane Hydrogels for Wound Healing.

Drug-loading hydrogels are promising candidates in the bioengineering research field; nevertheless, hydrophobic drug loading into a hydrophilic carrier system remains unsolved and is full of challenges. In this work, following the potential dual interactions between peptides and aromatic drugs, we developed a potent hybrid hydrogel formation method, namely, "peptide-/drug-directed self-assembly". The hybrid hydrogels were synthesized using polyethylene glycol (PEG)-based Fmoc-FF peptide hybrid polyurethane, in which curcumin could be encapsulated through self-assembly with Fmoc-FF peptide via π-π stacking. On the basis of this, curcumin loading capacity could be improved to as high as 3.3 wt % with sustained release. In addition, the curcumin loading enhanced the hydrogel mechanical properties from 4 kPa to over 10 kPa, similar to that of natural soft tissues. Furthermore, the hydrogels were injectable with self-healing properties since the Fmoc-FF peptide/curcumin coassembly was noncovalent and reversible. Spectroscopy results confirmed the existence of the coassembly of Fmoc-FF peptide/curcumin. Further in vivo experiments effectively demonstrated that the hydrogels could improve the cutaneous wound healing in a full-thickness skin defected model. This peptide-/drug-directed self-assembly of hybrid polyurethane hydrogel could be used as a promising platform for tissue-engineering scaffold and biomedical application.

Green Tea Polyphenol Induced Mg2+-rich Multilayer Conversion Coating: Toward Enhanced Corrosion Resistance and Promoted in Situ Endothelialization of AZ31 for Potential Cardiovascular Applications.

As a promising biodegradable metallic material, magnesium (Mg) and its alloys have attracted special attention in the recent decade. However, challenges still remain due to its high corrosion rate and insufficient biocompatibility after implantation. In this work, we prepare a simple and versatile green tea phenol-metal induced multilayer conversion coating (Mg2+ incorporated epigallocatechin gallate (EGCG) coating) on magnesium alloys' (AZ31) substrate by layer-by-layer (LBL) method. The surface morphology results revealed that, with the incorporation of Mg2+, the as-formed EGCG/Mg coating was rich in phenol-Mg complex and presented more homogeneous and dense morphology, with far less cracks than the pure EGCG coating. The in vitro degradation rate and corrosion resistance were studied by electrochemical corrosion tests and monitoring of the changed pH value and hydrogen evolution, respectively, which revealed that the corrosion rate was effectively decreased compared to that of bare AZ31 after it was protected by EGCG/Mg coating. In vitro and ex vivo thrombogenicity test demonstrated the EGCG/Mg coatings presented an impressive improvement in decreasing the adhesion and activation of platelets and erythrocytes, in activated partial thromboplastin time (APTT), and in antithrombogenicity compared to those of bare AZ31. Owing to the mild degradation rate, in combination with the biological function of EGCG, enhanced endothelial cells' (ECs') adhesion and proliferation, suppressed smooth muscle cells' (SMCs') adhesion/proliferation, and inhibited cytokine release were observed on EGCG/Mg coated AZ31 alloy. Besides, the in vivo subcutaneous embedding experiment suggested that the EGCG/Mg coating performed more mild tissue response due to the improved corrosion resistance to the surrounding microenvironment. Moreover, for in vivo abdominal aorta assay, the EGCG/Mg coated AZ31 wire presented better corrosion resistance and enhanced re-endothelialization compared to bare AZ31 wire. These results suggested the potential of using green tea polyphenol induced Mg2+-rich multilayer conversion coating for enhanced corrosion protection and desired biocompatibility of biodegradable cardiovascular implants.

Immobilization of nano Cu-MOFs with polydopamine coating for adaptable gasotransmitter generation and copper ion delivery on cardiovascular stents.

In-stent restenosis is worsened by thrombosis, acute inflammation, and uncontrollable smooth muscle cells (SMCs) proliferation at the early stage of implantation. Tailoring the stent surface can inhibit thrombosis, intimal hyperplasia, and accelerate re-endothelialization. In situ nitric oxide (NO) generation is considered as a promising method to improve anti-coagulation and anti-hyperplasia abilities. Copper based metal organic frameworks showed great potential as catalysts for NO generation, and copper ion (Cu2+) was demonstrated to promote endothelial cells (ECs) growth. Herein, by using polydopamine as the linker and coating matrix, nanoscale copper-based metal organic frameworks (nano Cu-MOFs) were immobilized onto the titanium surface for simultaneous nitric oxide (NO) catalytic generation and Cu2+ delivery. The nano Cu-MOFs-immobilized coating exhibited desirable NO release and adaptable Cu2+ delivery. Such coating inhibited platelet aggregation and activation via NO-cGMP signaling pathway, and significantly reduced thrombosis in an ex vivo extracorporeal circulation model. NO release and Cu2+ delivery showed synergetic effect to promote EC proliferation. Moreover, SMCs and macrophage proliferation was suppressed by the nano Cu-MOFs-immobilized coating, thereby reducing neointimal hyperplasia in vivo. Overall, this biocompatible coating is convenient for the surface modification of cardiovascular stents and effectively prevents the late stent thrombosis and in-stent restenosis associated with stent implantation.

Micelle-embedded coating with ebselen for nitric oxide generation.

Nitric oxide generation is considered to be a key factor to mimic endothelial function in terms of anti-coagulation and anti-hyperplasia. Herein, ebselen which could play the similar role as glutathion peroxidase-like was loaded into micelles and was further assembled into a layer-by-layer coating. The ability of nitric oxide generation and corresponding biological effect were investigated. Endothelial-mimetic surface has now attracted huge attention in blood-contacting materials, due to its inherent ability of secreting nitric oxide. Among those categories, nitric oxide generation surface is considered to be safe and tunable in the modification of vascular biomedical devices. How to adsorb or immobilize glutathion peroxidase-like catalyst and maintain sustained/safe nitric oxide generation is full of interest. This study aimed at developing a functional coating constructed via layer-by-layer assembly to introduce the catalyst into the coating by pre-loading ebselen in micelles. We firstly introduced phenylboronic acid moiety into the micelle molecule backbone and grafted catechol moiety to chitosan backbone. Then, chitosan, micelles (containing ebselen) and heparin were adopted as polyelectrolytes and then alternatively assembled onto the substrate via layer-by-layer protocol. The catechol was conjugated to the amine groups of chitosan by Schiff base reaction to synthesize chitosan-catechol. The hydrophobic cholesterol was conjugated to the one end of the hydrophilic hyaluronic acid, and the hydroxymethylphenylboronic acid was conjugated to the other end via the esterification of carboxyl (-COOH) and hydroxyl (-OH). The modified hyaluronic acid could spontaneously form micelles in aqueous solution. Ebselen was the loaded into the as-prepared micelles. Chitosan-catechol, heparin, and micelles were alternatively assembled onto the substrate layer by layer to form a micelle-embedded coating. The micelle-embedded coating with ebselen was successfully obtained and the nitric oxide generation ability was in a safe level which was close to healthy endothelial cells. The coating could effectively inhibit platelet adhesion and smooth muscle cell proliferation. The use of ebselen preloaded into micelles could provide a sustained release of catalyst for in situ nitric oxide generation. Besides, this method could also be used to load diverse drugs and regulate desired properties. The study was approved by the Institutional Review Board of the West China Hospital in Sichuan University on March 3, 2018, with approval No. K2018044.

Micelle-Embedded Layer-by-Layer Coating with Catechol and Phenylboronic Acid for Tunable Drug Loading, Sustained Release, Mild Tissue Response, and Selective Cell Fate for Re-endothelialization.

Tunable/sustained drug loading/releasing are of significance in addressing low cytotoxicity, long-term performance, and localized mild healing response in biomedical applications. With an ingenious design, a self-healing sandwiched layer-by-layer (LBL) coating was constructed by using chitosan/heparin as adopted polyelectrolytes with embedding of micelles, in which the chitosan backbone was grafted with catechol and the micelle was modified with exposed phenylboronic acid, endowing the coating with enhanced stability by abundant interactions among coating components (e.g., boric acid ester bond formation, weak intermolecular cross-linking, π-π interactions, and H-bonding). Moreover, rapamycin and atorvastatin calcium were selected as drug candidates and loaded into micelles, followed by drug-releasing behavior study. It was found that the LBL coating maintained a linear growth mode up to 30 cycles, giving a favorable tunability of coating construction and drug loading. The coating could also support sustained release of payloads and provide wild tissue response. With the systematic in vitro and in vivo study, such catechol-phenylboronic acid-enhanced LBL coating with drug loading would also address enhanced antiplatelet adhesion/activation and direct cell fate of endothelial cells and smooth muscle cells via tuning of coating cycles and loaded drugs. With modular assembly, such coating indicated potential for achieving enhanced re-endothelialization for vascular implants.