RESUMEN
Stenting is the primary treatment for vascular obstruction-related cardiovascular diseases, but it inevitably causes endothelial injury which may lead to severe thrombosis and restenosis. Maintaining nitric oxide (NO, a vasoactive mediator) production and grafting endothelial glycocalyx such as heparin (Hep) onto the surface of cardiovascular stents could effectively reconstruct the damaged endothelium. However, insufficient endogenous NO donors may impede NO catalytic generation and fail to sustain cardiovascular homeostasis. Here, a dopamine-copper (DA-Cu) network-based coating armed with NO precursor L-arginine (Arg) and Hep (DA-Cu-Arg-Hep) is prepared using an organic solvent-free dipping technique to form a nanometer-thin coating onto the cardiovascular stents. The DA-Cu network adheres tightly to the surface of stents and confers excellent NO catalytic activity in the presence of endogenous NO donors. The immobilized Arg functions as a NO fuel to generate NO via endothelial nitric oxide synthase (eNOS), while Hep works as eNOS booster to increase the level of eNOS to decompose Arg into NO, ensuring a sufficient supply of NO even when endogenous donors are insufficient. The synergistic interaction between Cu and Arg is analogous to a gas station to fuel NO production to compensate for the insufficient endogenous NO donor in vivo. Consequently, it promotes the reconstruction of natural endothelium, inhibits smooth muscle cell (SMC) migration, and suppresses cascading platelet adhesion, preventing stent thrombosis and restenosis. We anticipate that our DA-Cu-Arg-Hep coating will improve the quality of life of cardiovascular patients through improved surgical follow-up, increased safety, and decreased medication, as well as revitalize the stenting industry through durable designs.
Asunto(s)
Óxido Nítrico , Trombosis , Humanos , Óxido Nítrico/metabolismo , Cobre , Calidad de Vida , Stents/efectos adversos , Endotelio , Trombosis/prevención & control , Trombosis/etiologíaRESUMEN
Stent thrombosis (ST) is a catastrophic event and efforts to reduce its incidence by altering blood-stent interactions are longstanding. A new electret coating technology that produces long-lasting negative charge on stent surface could make them intrinsically resistant to thrombosis. We assessed the thrombogenicity of stents using an annular perfusion model with confocal microscopy, and determined the efficacy of electret coating technology to confer thrombo-resistant properties to standard stents. Using an annular perfusion chamber, Bare Metal Stent (BMS), standard uncoated DES (DES), and Electret-coated DES (e-DES) were exposed to human blood under arterial flow conditions. Deposits of fibrinogen and platelets on the stent surface were analyzed using immunofluorescence staining and confocal microscopy. Surface coverage by fibrinogen and platelets and the deposit/aggregate size were quantified using computerized morphometric analysis. The experimental methodology produced consistent, quantifiable results. Area of stent surface covered by fibrinogen and platelets and the average size of the deposits/aggregates were lowest for e-DES and highest on BMS, with DES in the middle. The size of fibrinogen-deposits showed no differences between the stents. The testing methodology used in our study successfully demonstrated that electret coating confers significant antithrombotic property to DES stents. These findings warrant confirmation in a larger study.
Asunto(s)
Stents Liberadores de Fármacos/normas , Trombosis/terapia , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Prueba de Estudio Conceptual , Resultado del TratamientoRESUMEN
Medical devices directly exposed to blood are commonly used to treat cardiovascular diseases. However, these devices are associated with inflammatory reactions leading to delayed healing, rejection of foreign material or device-associated thrombus formation. We developed a novel recombinant fusion protein as a new biocompatible coating strategy for medical devices with direct blood contact. We genetically fused human serum albumin (HSA) with ectonucleoside triphosphate diphosphohydrolase-1 (CD39), a promising anti-thrombotic and anti-inflammatory drug candidate. The HSA-CD39 fusion protein is highly functional in degrading ATP and ADP, major pro-inflammatory reagents and platelet agonists. Their enzymatic properties result in the generation of AMP, which is further degraded by CD73 to adenosine, an anti-inflammatory and anti-platelet reagent. HSA-CD39 is functional after lyophilisation, coating and storage of coated materials for up to 8 weeks. HSA-CD39 coating shows promising and stable functionality even after sterilisation and does not hinder endothelialisation of primary human endothelial cells. It shows a high level of haemocompatibility and diminished blood cell adhesion when coated on nitinol stents or polyvinylchloride tubes. In conclusion, we developed a new recombinant fusion protein combining HSA and CD39, and demonstrated that it has potential to reduce thrombotic and inflammatory complications often associated with medical devices directly exposed to blood.
RESUMEN
To reduce the risk of intra-stent restenosis and improve hemocompatibility of biomaterials, the therapeutic re-endothelialization is required. Indeed, the behavior of endothelial cells is affected by several factors such as wettability and surface energy of biomaterial in contact with cells and blood. The aim of this study was to evaluate the physicochemical and biological properties of new polymers derived from poly((R,S)-3,3-dimethylmalic acid) (PDMMLA) that will be used as cardiovascular stents coating. In fact, a comprehensive study of the roughness and topography and the thermal and rheological properties of these materials were investigated. Furthermore, this was correlated with the biological response of human vascular endothelial cells (HUVECs) and monocytes (MM6) to these biomaterials. Our results revealed very interesting surface properties of PDMMLAs, excellent thermal and thermo-mechanical properties and a suitable biological response. All these properties can be adjusted by simple chemical modification of the side chain of the studied polymers.
Asunto(s)
Células Endoteliales , Stents , Materiales Biocompatibles/farmacología , Humanos , Polímeros , Propiedades de SuperficieRESUMEN
Cardiovascular diseases are the most distributed cause of death worldwide. Stenting of arteries as a percutaneous transluminal angioplasty procedure became a promising minimally invasive therapy based on re-opening narrowed arteries by stent insertion. In order to improve and optimize this method, many research groups are focusing on designing new or improving existent stents. Since the beginning of the stent development in 1986, starting with bare-metal stents (BMS), these devices have been continuously enhanced by applying new materials, developing stent coatings based on inorganic and organic compounds including drugs, nanoparticles or biological components such as genes and cells, as well as adapting stent designs with different fabrication technologies. Drug eluting stents (DES) have been developed to overcome the main shortcomings of BMS or coated stents. Coatings are mainly applied to control biocompatibility, degradation rate, protein adsorption, and allow adequate endothelialization in order to ensure better clinical outcome of BMS, reducing restenosis and thrombosis. As coating materials (i) organic polymers: polyurethanes, poly(ε-caprolactone), styrene-b-isobutylene-b-styrene, polyhydroxybutyrates, poly(lactide-co-glycolide), and phosphoryl choline; (ii) biological components: vascular endothelial growth factor (VEGF) and anti-CD34 antibody and (iii) inorganic coatings: noble metals, wide class of oxides, nitrides, silicide and carbide, hydroxyapatite, diamond-like carbon, and others are used. DES were developed to reduce the tissue hyperplasia and in-stent restenosis utilizing antiproliferative substances like paclitaxel, limus (siro-, zotaro-, evero-, bio-, amphi-, tacro-limus), ABT-578, tyrphostin AGL-2043, genes, etc. The innovative solutions aim at overcoming the main limitations of the stent technology, such as in-stent restenosis and stent thrombosis, while maintaining the prime requirements on biocompatibility, biodegradability, and mechanical behavior. This paper provides an overview of the existing stent types, their functionality, materials, and manufacturing conditions demonstrating the still huge potential for the development of promising stent solutions.
RESUMEN
Even though drug-eluting stent (DES) has prominently reduced restenosis, however, its complication of delayed endothelialization has caused chronic side effect. A coating of ginseng-based biodegradable polymer could address this issue due to its specific therapeutic values. However, deposition of this type of stable coating on metallic implant often scarce. Therefore, in this study, different polyaniline (PANI) emeraldine compositions were adopted to electrodeposit ginsenoside encapsulated poly(lactic-co-glycolic acid) microcapsules coating. The coating surfaces were analyzed using attenuated total reflectance-Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, contact angle, and atomic force microscopy instruments. A month coating stability was then investigated with an evaluation of in vitro human umbilical vein endothelial cell analyses consisted of cytotoxicity and cells attachment assessments. The 1.5 mg PANI emeraldine has assisted the formation of stable, uniform, and rounded microcapsules coating with appropriate wettability and roughness. Less than 1.5 mg PANI emeraldine was not enough to drive the formation of microcapsules coating while greater than 1.5 mg caused the deposition of melted microcapsules. The similar coating also has promoted greater cells proliferation and attachment compared to other coating variation. Therefore, the utilization of electrodeposition to deposit a drug-based polymer coating could be implemented to develop DES, in accordance to stent implantation which ultimately aims for enrich endothelialization.
Asunto(s)
Compuestos de Anilina/química , Derivados del Benceno/química , Materiales Biocompatibles Revestidos/química , Ginsenósidos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Compuestos de Sulfhidrilo/química , Cápsulas , Stents Liberadores de Fármacos , Galvanoplastia , Células Endoteliales de la Vena Umbilical Humana , Humanos , HumectabilidadRESUMEN
BACKGROUND: Local delivery of anti-cancer drugs through a stent is a very promising and anticipated treatment modality for patients who have obstructions in their gastrointestinal tract with malignant tumors. Anticancer drug release via stents, however, needs to be optimized with respect to drug delivery behavior for the stents to be effective for prolonged containment of tumor proliferation and stent re-obstruction. Local stent-based drug delivery has been tested using an effective anti-cancer drug, gemcitabine, but the release from the stent-coated polyurethane films is often too fast and the drug is depleted from the coated film virtually in a day. METHODS: To moderate the drug release from a polyurethane film, a gemcitabine-incorporated polyurethane film was enveloped with a pure polyurethane film, with no drug loading, and with a silicone film by solution casting after activation of the silicone film surface with plasma treatment. RESULTS: The pure polyurethane barrier film was effective; the interface of the two were indistinguishable on scanning electron microscopy, and the initial burst, i.e., the cumulative release in a day, decreased from 90 to 26%. The silicone film barrier, on the other hand, was defective as voids were seen using a scanning electron microscope, and micro-separation of the two layers was observed after the film was immersed in phosphate-buffered saline for 1 day during the in vitro drug release study. CONCLUSIONS: Enveloping a gemcitabine-releasing polyurethane film with a homo-polymer barrier film was quite effective for moderating the initial burst of gemcitabine, thus, prolonging the release time of the drug. Enveloping the polyurethane film with a silicone film was also possible after plasma treatment of the silicone film surface, but the two films eventually separated in the aqueous environment. More studies are needed to tune the drug release behavior of gemcitabine from the stent covering film before attempting a clinical application of an anti-cancer drug releasing stent.
RESUMEN
Vascular implants remain clinically challenged due to often-occurring thrombosis and stenosis. Critical to addressing these complications is the design of implant material surfaces to inhibit the activities of platelets, smooth muscle cells (SMCs) and inflammatory cells. Recent mechanobiology studies accentuate the significance of material elasticity to cells and tissues. We thus developed and characterized an implant coating composed of hybrid, viscoelastic microfibers with coaxial core-sheath nanostructure. The coating over metallic stent material was formed by first depositing coaxially-electrospun fibers of poly(L-lactic acid) core and polyethylene glycol dimethacrylate sheath, and then polymerizing fibers with various UV times. Material characterizations were performed to evaluate the coating structure, mechanical property and biocompatibility. Results showed that coaxial microfibers exhibited arterial-like mechanics. The soft surface, high water content and swelling ratio of the coaxial fibers resemble hydrogels, while they are mechanically strong with an elastic modulus of 172-729â¯kPa. The coating strength and surface elasticity were tunable with the photopolymerization time. Further, the elastic fibers, as conformal coating on stent metal, strongly reduced SMC overgrowth and discouraged platelet adhesion and activation, compared to bare metals. Importantly, after 7-day subcutaneous implantation, coaxial fiber-coated implants showed more favorable in vivo responses with reduced tissue encapsulation, compared to bare stent metals or those coated with a two-layered fiber mixture composed of fibers from individual polymers. The excellent biocompatibility aroused from nanostructural interfaces of hybrid fibers offering hydrated, soft, nonfouling microenvironments. Such integrated fiber system may allow creation of advanced vascular implants that possess physico-mechanical properties of native arteries.
Asunto(s)
Prótesis Vascular , Materiales Biocompatibles Revestidos/química , Hidrogeles/química , Metacrilatos/química , Nanofibras/química , Poliésteres/química , Polietilenglicoles/química , Animales , Plaquetas/citología , Plaquetas/efectos de los fármacos , Bovinos , Supervivencia Celular/efectos de los fármacos , Materiales Biocompatibles Revestidos/farmacología , Materiales Biocompatibles Revestidos/efectos de la radiación , Elasticidad , Técnicas Electroquímicas , Hidrogeles/farmacología , Hidrogeles/efectos de la radiación , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Nanofibras/efectos de la radiación , Nanofibras/ultraestructura , Adhesividad Plaquetaria/efectos de los fármacos , Polimerizacion , Cultivo Primario de Células , Ratas , Propiedades de Superficie , Rayos Ultravioleta , ViscosidadRESUMEN
Here we developed a semi-interpenetrating network (IPN) hydrogel obtained by free radical polymerization to fabricate a coated stent with the aim of incorporating a natural topography present in the human body to improve biological activity. The method involves sandwiching a bare metal stent in the semi-IPN hydrogel via solution cast molding. The bio-functionality of the membrane could be tuned by incorporating Polydopamine into the matrix, and also the mechanical property was optimized by choosing an adequate concentration of acrylamide. The coating containing polydopamine hydrogel showed good mechanical stability under continuous flow condition, as demonstrated by crimping and deployment into a catheter without damage. Stent polymer bonding was enhanced via polydopamine incorporation in the matrix. The non-thrombogenicity of the coating containing hydrogel was confirmed through dynamic hemocompatibility studies in vitro. Vascular simulations, including other biomechanical performance, like durability testing, radial strength, and recoil, were demonstrated. The dopamine containing hydrogel membrane (DCHM) was found to promote cell material interaction due to the ability of the catechol to bind protein and induce HUVECs cytoplasmic spreading, proliferation, and migration, with reduced smooth muscle cell (SMCs) activity. SMCs inhibition correlated well with the amount of incorporated catechol in the matrix. Our results show that this material used as coated stent could be more effective in suppressing platelet aggregation with improved haemocompatibility/biocompatibility for faster re-endothelialization than bare metal stent (BMS).
Asunto(s)
Materiales Biocompatibles Revestidos/farmacología , Hidrogeles/farmacología , Polímeros/farmacología , Stents , Trombosis/patología , Adsorción , Arterias/fisiología , Materiales Biomiméticos/química , Pruebas de Coagulación Sanguínea , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Análisis de Elementos Finitos , Hemodinámica/efectos de los fármacos , Hemólisis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Indoles/farmacología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Adhesividad Plaquetaria/efectos de los fármacos , Resistencia a la TracciónRESUMEN
The field of percutaneous coronary intervention has seen a plethora of advances over the past few decades, which have allowed for its development into safe and effective treatments for patients suffering from cardiovascular diseases. However, stent thrombosis and in-stent restenosis remain clinically significant problems. Herein, we describe the synthesis and characterization of fibrous polymer coatings on stent material nitinol, in the hopes of developing a more suitable stent surface to enhance re-endothelialization. Electrospinning technique was used to fabricate polyethylene glycol dimethacrylate/poly l-lactide acid (PEGDMA/PLLA) blend fiber substrate with tunable elasticity and hydrophilicity for use as coatings. Attachment of platelets and arterial smooth muscle cells (SMC) onto the coatings as well as the secretory effect of mesenchymal stem cells cultured on the coatings on the proliferation and migration of arterial endothelial cells and SMCs were assessed. It was demonstrated that electrospun PEGDMA/PLLA coating with 1:1 ratio of the components on the nitinol stent-reduced platelet and SMC attachment and increased stem cell secretory factors that enhance endothelial proliferation. We therefore postulate that the fibrous coating surface would possess enhanced biological compatibility of nitinol stents and hold the potential in preventing stent failure through restenosis and thrombosis.
Asunto(s)
Materiales Biocompatibles Revestidos/química , Metacrilatos/química , Poliésteres/química , Polietilenglicoles/química , Stents , Aleaciones , Animales , Pruebas de Coagulación Sanguínea , Plaquetas/fisiología , Adhesión Celular , Proliferación Celular , Supervivencia Celular , Elasticidad , Células Endoteliales/citología , Células Endoteliales/fisiología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Miocitos del Músculo Liso/fisiología , Nanofibras/química , Arteria Pulmonar/citología , Ratas , Propiedades de SuperficieRESUMEN
The gelling behaviors of thiolated chitosan (TCS) in alkaline condition were investigated. Thioglycolic acid was conjugated onto chitosan backbone through amide bond formation. The variations of thiol group content were monitored in presence of H2O2 or different pH values (pH 7.0, 8.0, 9.0) in dialysis mode. Different from the decreasing thiol group content upon time in acidic condition, increasing amount of thiol groups was detected in alkaline pH during 120 min dialysis attributed to alkaline hydrolysis of intra-molecular disulfide bonds. The extent of which was larger at higher pH values. Higher degree of thiolation, thiomer concentration or pH values promoted gelation of TCS. Entanglement and coagulation of chitosan molecule chains and re-arrangement of disulfide bonds acted closely and dynamically in the gelation process. Disulfide bonds, especially inter-molecular type, are formed by synergetic effects of thiol/disulfide interchange and thiol/thiol oxidation reactions. TCS coated vascular stent displayed wave-like microstructure of parallel ridges and grooves, which favored HUVECs adhesion and proliferation. The biocompatibility, peculiar morphology and thiol moieties of TCS as stent coating material appear application potential for vascular stent.
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Quitosano/química , Stents , Compuestos de Sulfhidrilo/química , Adhesión Celular/efectos de los fármacos , Quitosano/toxicidad , Geles , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/química , Concentración de Iones de Hidrógeno , Oxidación-Reducción , Transición de FaseRESUMEN
Functional graded nanobiomembranes (FGMs) with multiple layers were created by a single process using a novel electrospinning system equipped with a generator and a PCI type motion board as a controller in order to control the drug release rate. By varying physical apparatus-related parameters such as nozzle-to-collector distance via a robot and the collector moving velocity the FGMs were formed. For the membrane base layer, poly-(ε-caprolactone) (PCL) with paclitaxel (PTX) was dissolved in a solvent (dichloromethane, N,N-dimethylformamide) and electrospun. For the top layers, the PCL solution was electrospun according to the distance and FGM system parameters, which can move the collector location at a constant ratio. It was observed that pore size, porosity, and permeability were higher when the membrane was spun at the far distance. The top surface of FGM is more porous, rougher, more permeable, and more hydrophilic so as to be active to the surrounding tissue cells. Meanwhile, the porous inside membrane was as low as the membrane spun at a close distance. Thus it induced a slow drug release due to the internal structure of FGM, which is considered to be very effective for slow drug release as well as bioactivity and bioconductivity.
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Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Membranas Artificiales , Nanopartículas/química , Paclitaxel/farmacología , Nanopartículas/ultraestructura , Permeabilidad , Poliésteres/química , Porosidad , Espectroscopía Infrarroja por Transformada de Fourier , AguaRESUMEN
Vascular gene-eluting stents (GES) is a promising strategy for treatment of cardiovascular disease. Very recently, we have proved that the (protamine sulfate/plasmid DNA encoding hepatocyte growth factor) (PrS/HGF-pDNA) multilayer can serve as a powerful tool for enhancing competitiveness of endothelial cell over smooth muscle cell, which opens perspectives for the regulation of intercellular competitiveness in the field of interventional therapy. However, before the gene multilayer films could be used in vascular stents for real clinical application, the preservation of gene bioactivity during the industrial sterilization and the hemocompatibility of film should be taken into account. Actually, both are long been ignored issues in the field of gene coating for GES. In this study, we demonstrate that the (PrS/HGF-pDNA) multilayer film exhibits the good gene-protecting abilities, which is confirmed by using the industrial sterilizations (gamma irradiation and ethylene oxide) and a routine storage condition (dry state at 4°C for 30 days). Furthermore, hemocompatible measurements (such as platelet adhesion and whole blood coagulation) and antibacterial assays (bacteria adhesion and growth inhibition) indicate the good anticoagulation and antibacterial properties of the (PrS/HGF-pDNA) multilayer film. The in vivo preliminary data of angiography and histological analysis suggest that the (PrS/HGF-pDNA) multilayer coated stent can reduce the in-stent restenosis. This work reveals that the (PrS/HGF-pDNA) multilayer film could be a promising candidate as coating for GES, which is of great potential in future clinic application.
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Antibacterianos , Anticoagulantes , ADN , Stents Liberadores de Fármacos , Técnicas de Transferencia de Gen , Oclusión de Injerto Vascular/prevención & control , Factor de Crecimiento de Hepatocito , Plásmidos , Protaminas , Animales , Antibacterianos/química , Antibacterianos/farmacología , Anticoagulantes/química , Anticoagulantes/farmacología , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , ADN/química , ADN/farmacología , Masculino , Ensayo de Materiales , Plásmidos/química , Plásmidos/farmacología , Protaminas/química , Protaminas/farmacología , ConejosRESUMEN
Antibody-coated stents to capture circulating endothelial progenitor cells (EPCs) for re-endothelialization appear to be a novel therapeutic option for the treatment of atherosclerotic disease. Hydroxybutyl chitosan (HBC), a linear polysaccharide made from shrimps and other crustacean shells, is biocompatible, nontoxic, and hydrophilic, making it ideal for biomedical applications. In this study, HBC was explored for the immobilization of anti-CD133 antibodies. We demonstrated that CD133 antibodies mediated by HBC were successfully coated on cobalt-chromium alloy discs and metal stents. The coating was homogeneous and smooth as shown by electronic microscopy analysis. Balloon expansion of coated stents did not cause cracking or peeling. The HBC discs promoted CD133+ EPCs and human umbilical vein endothelial cell growth in vitro. The CD133 antibody-coated but not bare discs bound CD133+ EPCs in vitro. Implantation of CD133 antibody-coated stents significantly inhibited intimal hyperplasia and reduced restenosis compared with implantation of bare stents in a porcine model of atherosclerosis. These findings suggest HBC is a valuable anchoring agent that can be applied for bioactive coating of stents and that CD133 antibody-coated stents might be a potential therapeutic alternative for the treatment of atherosclerotic disease.