Pengkai Qi

Mussel-inspired one-step adherent coating rich in amine groups for covalent immobilization of heparin: hemocompatibility, growth behaviors of vascular cells, and tissue response.

Heparin, an important polysaccharide, has been widely used for coatings of cardiovascular devices because of its multiple biological functions including anticoagulation and inhibition of intimal hyperplasia. In this study, surface heparinization of a commonly used 316L stainless steel (SS) was explored for preparation of a multifunctional vascular stent. Dip-coating of the stents in an aqueous solution of dopamine and hexamethylendiamine (HD) (PDAM/HD) was presented as a facile method to form an adhesive coating rich in primary amine groups, which was used for covalent heparin immobilization via active ester chemistry. A heparin grafting density of about 900 ng/cm(2) was achieved with this method. The retained bioactivity of the immobilized heparin was confirmed by a remarkable prolongation of the activated partial thromboplastin time (APTT) for about 15 s, suppression of platelet adhesion, and prevention of the denaturation of adsorbed fibrinogen. The Hep-PDAM/HD also presented a favorable microenvironment for selectively enhancing endothelial cell (EC) adhesion, proliferation, migration and release of nitric oxide (NO), and at the same time inhibiting smooth muscle cell (SMC) adhesion and proliferation. Upon subcutaneous implantation, the Hep-PDAM/HD exhibited mitigated tissue response, with thinner fibrous capsule and less granulation formation compared to the control 316L SS. This number of unique functions qualifies the heparinized coating as an attractive alternative for the design of a new generation of stents.

A biocompatible and functional adhesive amine-rich coating based on dopamine polymerization

Amine groups physiologically play an important role in regulating the growth behavior of cells and they have technological advantages for the conjugation of biomolecules. In this work, we present a method to deposit a copolymerized coating of dopamine and hexamethylendiamine (HD) (PDAM/HD) rich in amine groups onto a target substrate. This method only consists of a simple dip-coating step of the substrate in an aqueous solution consisting of dopamine and HD. Using the technique of PDAM/HD coating, a high density of amine groups of about 30 nmol cm-2 was obtained on the target substrate surface. The PDAM/HD coating showed a high cross-linking degree that is robust enough to resist hydrolysis and swelling. As a vascular stent coating, the PDAM/HD presented good adhesion strength to the substrate and resistance to the deformation behavior of compression and expansion of a stent. Meanwhile, the PDAM/HD coating exhibited good biocompatibility and attenuated the tissue response compared with 316L stainless steel (SS). The primary amine groups of the PDAM/HD coating could be used to effectively immobilize biomolecules containing carboxylic groups such as heparin. These data suggested the promising potential of this PDAM/HD coating for application in the surface modification of biomedical devices.

Immobilization of DNA aptamers via plasma polymerized allylamine film to construct an endothelial progenitor cell-capture surface.

The endothelial progenitor cells (EPCs) capture stent has drawn increasing attentions and become one of the most promising concepts for the next generation vascular stent. In this regard, it is of great significance to immobilize a molecule with the ability to bind EPC for rapid in vivo endothelialization with high specificity. In this work, a facile two-step method aimed at constructing a coating with specific EPC capturing aptamers is reported. The processes involves as the first-step deposition of plasma polymerized allylamine (PPAam) on a substrate to introduce amine groups, followed by the electrostatic adsorption of a 34 bases single strand DNA sequence to the PPAam surface as a second step (PPAam-DNA). Grazing incidence attenuated total reflection Fourier transform infrared spectroscopy (GATR-FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed the successful immobilization of the aptamers. Quartz crystal microbalance with dissipation (QCM-D) real time monitoring result shows that about 175 ng/cm(2) aptamers were conjugated onto the PPAam surface. The interactions between the modified surfaces and human umbilical vein endothelial cells (ECs), smooth muscle cells (SMCs), and murine induced EPCs derived from mesenchymal stem cells (MSCs) were also investigated. It was demonstrated that PPAam-DNA samples could capture more EPCs, and present a cellular friendly surface for the proliferation of both EPCs and ECs but no effect on the hyperplasia of SMCs. Also, the co-culture results of 3 types of cells confirmed that the aptamer could specifically bond EPCs rather than ECs and SMCs, suggesting the competitive adhesion advantage of EPCs to ECs and SMCs. These data demonstrate that the EPC aptamer has large potential for designing an EPC captured stent and other vascular grafts with targeted in situ endothelialization.

Gallic Acid Tailoring Surface Functionalities of Plasma-Polymerized Allylamine-Coated 316L SS to Selectively Direct Vascular Endothelial and Smooth Muscle Cell Fate for Enhanced Endothelialization

The creation of a platform for enhanced vascular endothelia cell (VEC) growth while suppressing vascular smooth muscle cell (VSMC) proliferation offers possibility for advanced coatings of vascular stents. Gallic acid (GA), a chemically unique phenolic acid with important biological functions, presents benefits to the cardiovascular disease therapy because of its superior antioxidant effect and a selectivity to support the growth of ECs more than SMCs. In this study, GA was explored to tailor such a multifunctional stent surface combined with plasma polymerization technique. On the basis of the chemical coupling reaction, GA was bound to an amine-group-rich plasma-polymerized allylamine (PPAam) coating. The GA-functionalized PPAam (GA-PPAam) surface created a favorable microenvironment to obtain high ECs and SMCs selectivity. The GA-PPAam coating showed remarkable enhancement in the adhesion, viability, proliferation, migration, and release of nitric oxide (NO) of human umbilical vein endothelial cells (HUVECs). The GA-PPAam coating also resulted in remarkable inhibition effect on human umbilical artery smooth muscle cell (HUASMC) adhesion and proliferation. These striking findings may provide a guide for designing the new generation of multifunctional vascular devices.

Flow-induced corrosion of absorbable magnesium alloy: In-situ and real-time electrochemical study

An in-situ and real-time electrochemical study in a vascular bioreactor was designed to analyze corrosion mechanism of magnesium alloy (MgZnCa) under mimetic hydrodynamic conditions. Effect of hydrodynamics on corrosion kinetics, types, rates and products was analyzed. Flow-induced shear stress (FISS) accelerated mass and electron transfer, leading to an increase in uniform and localized corrosions. FISS increased the thickness of uniform corrosion layer, but filiform corrosion decreased this layer resistance at high FISS conditions. FISS also increased the removal rate of localized corrosion products. Impedance-estimated and linear polarization-measured polarization resistances provided a consistent correlation to corrosion rate calculated by computed tomography.

Polydopamine-mediated long-term elution of the direct thrombin inhibitor bivalirudin from TiO2 nanotubes for improved vascular biocompatibility

Thrombosis and restenosis are two major complications associated with current commercial vascular stents. In situ regeneration of a healthy endothelium has been recognized as a promising strategy to address these issues. Numerous strategies have been explored for this goal. However, in most of the cases, they only focused on enhancing endothelial cell growth, ignoring antithrombotic requirements and the competition between smooth muscle cells (SMCs) and endothelial cells (ECs) for their growth. This resulted in non-satisfying clinical results. In this study, we created a multifunctional surface that meets the need of antithrombosis and re-endothelialization. A nanotubular titanium oxide (TiO2) system has been developed, which elutes the direct thrombin inhibitor, bivalirudin (BVLD); moreover, polydopamine (PDAM) is used to tailor the surface functionality of TiO2 nanotubes (NTs) for controlling the elution of BVLD. PDAM-functionalized TiO2 NTs controls the BVLD for more than two months. BVLD eluted from NTs was bioactive and showed a substantial inhibitory effect on thrombin bioactivity, platelet adhesion and activation. In addition, the BVLD-eluting nanotubular TiO2 system has high selectivity to enhance human umbilical vein endothelial cell (HUVEC) growth, while it inhibits human umbilical artery smooth muscle cell (HUASMC) proliferation. Our design strategy for the BVLD-eluting nanotubular TiO2 system creates a favorable microenvironment for durable thromboresistance and the promotion of re-endothelialization, and thus it is suitable for the long-term treatment of cardiovascular diseases.

New strategies for developing cardiovascular stent surfaces with novel functions (Review)

In this review, the authors summarize the developments in surface modification of cardiovascular materials especially in authors laboratory. The authors focus on three different strategies to construct multifunctional surfaces including coimmobilization of various biomolecules on stent surfaces, stem cell based therapy systems, and a single-molecule multipurpose modification strategy in vascular interventional therapy. The roles of various molecules like heparin, gallic acid, various aptamers, and nitric oxide are highlighted in the new strategies for developing cardiovascular stent surfaces with novel functions including excellent hemocompatibility, inhibiting smooth muscle cells proliferation, and native endothelium regeneration. The success of these multifunctional surfaces provides the tremendous potential in designing the next generation of vascular stents.

Development of nitric oxide catalytic coatings by conjugating 3,3-disulfodipropionic acid and 3,3-diselenodipropionic acid for improving hemocompatibility.

Nitric oxide (NO), discovered as an endothelium-derived relaxing factor, has been found to have multiple intracellular effects in vascular diseases including vasorelaxation regulation, endothelial regeneration, inhibition of leukocyte chemotaxis, and platelet activation. In the work described here, the authors have developed a NO-catalytic bioactive coating for improving hemocompatibility. The authors first prepared a dopamine and hexamethylendiamine (PDAM/HD) amine-rich adherent copolymer coating to introduce amine groups onto 316L stainless steel, followed by covalently conjugating 3,3-disulfodipropionic acid (S-S) and 3,3-diselenodipropionic acid (Se-Se), which mimic glutathione peroxidase-like catalytic production of NO. S-S and Se-Se were immobilized on the PDAM/HD surface via carbodiimide coupling chemistry. X-ray photoelectron spectroscopy analysis revealed clear S2p and Se3d signals, confirming the immobilization of S-S and Se-Se on the PDAM/HD surface. The NO release behavior of different samples was investigated. In detail, two species of thionitrites (RSNO), S-nitrosoglutathione (GSNO, endogenous NO donors) and S-nitrosoacetylpenicillamine (SNAP) were chosen as NO donors to investigate the NO catalytic properties of S-S and Se-Se modified PDAM/HD surfaces. Not only Se-Se@PDAM/HD but also S-S@PDAM/HD coatings showed the ability to continuously catalyze RSNO to generate NO in the presence of proper thiol reducing agent. For the Se-Se@PDAM/HD coating, the NO release amount and rate were greater than S-S@PDAM/HD in both GSNO and SNAP conditions. The results showed that organosulfide species possesses NO catalytic ability as well as organoselenium species. The authors demonstrated that both S-S@PDAM/HD and Se-Se@PDAM/HD coatings exhibited outstanding inhibition effect on platelet adhesion, aggregation and activation via the cyclic guanylate monophosphate signal pathway. Thus these results suggested that NO catalytic coatings based on organoselenium and organosulfide species immobilization can help to improve hemocompatibility. NO-catalytic strategies possess huge potential applications in blood-contacting devices.

Facile immobilization of vascular endothelial growth factor on a tannic acid-functionalized plasma-polymerized allylamine coating rich in quinone groups

Biomolecules with thiol or amine groups can easily be covalently immobilized onto a substrate equipped with quinone groups in a mild alkali buffer solution based on Schiff base or Michael addition reactions. In this study, we reported a simple two-step approach to creating a functional coating with abundant quinone groups for facile immobilization of vascular endothelial growth factor (VEGF) in mild phosphate buffered saline (PBS, pH 7.4). This approach initially involved the deposition of an amine-bearing plasma-polymerized allylamine (PPAam) coating. Tannic acid (TA) was subsequently used for introducing phenolic hydroxylic hydroxyl/quinone groups. The results of water contact angles (WCAs), Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy analysis (XPS) revealed the effective conjugation of TA to PPAam, as well as the immobilization of VEGF to TA-functionalized PPAam (TA-PPAam). The result of a quartz crystal microbalance with dissipation (QCM-D) showed that 158 ± 13 ng cm−2 of VEGF was successfully immobilized onto the TA-PPAam surface. TA-PPAam bound with VEGF significantly enhanced human umbilical vein endothelial cell (HUVEC) proliferation, indicating the good retention of the bioactivity of VEGF. The TA-PPAam functional coating provided a novel, facile strategy for the covalent immobilization of biomolecules, especially growth factors, under mild reaction conditions.

Polydopamine Modified TiO2 Nanotube Arrays for Long-Term Controlled Elution of Bivalirudin and Improved Hemocompatibility

Sustained and controllable release characteristics are pivotal factors for novel drug delivery technologies. TiO2 nanotube arrays prepared by self-ordering electrochemical anodization are attractive for the development of biomedical devices for local drug delivery applications. In this work, several layers of polydopamine (PDA) were deposited to functionalize TiO2 nanotube arrays. The anticoagulant drug bivalirudin (BVLD) was used as a model drug. PDA extended the release period of BVLD and maintained a sustained release kinetic. Depending on the number of PDA layers, the release characteristics of BVLD improved, as there was a reduced burst release (from 45% to 11%) and extended overall release period from 40 days to more than 300 days in the case of 5 layers. Besides, the BVLD loaded 5-layer PDA coating maintained the high bioactivity of BVLD and effectively reduced the thrombosis formation by inhibition of the adhesion and denaturation of fibrinogen, platelets, and other blood components. Both in vitro and ex vivo blood evaluation results demonstrated that this coating significantly improved the hemocompatibility. These results confirmed the capability of PDA fitted TiO2 nanotube systems to be applied for local drug delivery over an extended period with well retained bioactivity and predictable release kinetics.