Cardiovascular diseases (CVD) is the leading causes of mortality globally. Various blood-contact medical devices, by applying anticoagulant coatings on the material surface. Utilizing various anticoagulants and enhancing the lubricity of medical device surfaces can effectively reduce short-term thrombotic risks. However, thrombosis in long-term or medium-to-long-term implanted devices remains a significant challenge. Current evidence suggests that during prolonged implantation, immune rejection of the device and its matrix, along with chronic inflammation induced by the disease, are key contributors to late-stage thrombosis. Therefore, modulating inflammation under pathological conditions is considered crucial for achieving long-term antithrombotic objectives. This review summarizes several representative antithrombotic coatings strategies based on anti-inflammatory and introduces some of the research contributions in this area.

Liquid-like surfaces have demonstrated immense potential in their ability to resist cell adhesion, a critical requirement for numerous applications across various domains. However, the conventional methodologies for preparing liquid-like surfaces often entail a complex multi-step polymer brush modification process, which is not only time-consuming but also presents significant challenges. In this work, we developed a single-cycle polymer brush modification strategy to build liquid-like surfaces by leveraging high-molecular-weight bis(3-aminopropyl)-terminated polydimethylsiloxane, which significantly simplifies the preparation process. The resultant liquid-like surface is endowed with exceptional slipperiness, effectively inhibiting bacterial colonization and diminishing the adherence of platelets. Moreover, it offers promising implications for reducing the dependency on anticoagulants in microfluidic systems constructed from PDMS, all while sustaining its antithrombotic attributes.

A functional liquid-infused catheter surface strategy has recently attracted increasing attention for blood transport with the remarkable antibiofouling performance. Nevertheless, constructing porous structure inside a catheter with effective functional liquid-locking ability remains extremely challenging. Herein, the central cylinder mold and sodium chloride particle templates technique was used to create a PDMS sponge-based catheter that stores a stable functional liquid. Our multifunctional liquid-infused PDMS sponge-based catheter can not only exhibit bacterial resistant, less macrophages infiltration, a slighter inflammation response, but also capability to prevent platelet adhesion and activation, and impressively reduce thrombosis in vivo even at high shear. Therefore, these desirable properties will endow the prospective practical applications and serve as a watershed moment in the development of biomedical devices.

Magnesium alloys have attracted considerable interest as prospective biodegradable materials in cardiovascular stents because of their metal mechanical properties and biocompatibility. However, fast degradation and slow endothelialization results in the premature disintegration of mechanical integrity and the restenosis of implanted Mg-based stents, which is the primary hurdle limiting their predicted clinical applicability. The development of bioinspired strategies is a burgeoning area in cardiovascular stents’ fields of research. Inspired by the unique features of lotus leaves, pitcher plants, healthy endothelial cells (ECs), marine mussels, and extracellular matrix, various bioinspired strategies have been developed to build innovative artificial materials with tremendous promise for medicinal applications. This perspective focuses on bioinspired strategies to provide innovative ideas for reducing corrosion resistance and accelerating endothelialization. The bioinspired strategies are envisaged to serve as a significant reference for future research on Mg-based medical devices.

Magnesium alloys are regarded as potential candidates in industrial and biomedical applications because of their excellent mechanical properties and biodegradability. However, the excessive degradation rate of magnesium alloys can cause a premature disintegration of mechanical integrity, which is the main bottleneck that limits applications. Inspired by nature, various novel surface designs provide a clever strategy to regulate the corrosion behavior of magnesium alloys. This review extensively discusses bioinspired surface designs to reduce corrosion resistance and realize functionalization, so as to offer new ideas with great potential for biomedical applications. Future research on corrosion resistance is expected to benefit greatly from the bioinspired surface designs.

Vascular stent implantation is the primary treatment for coronary artery disease. Surface modification of coronary stents is a topic of interest to prevent thrombosis and restenosis and to promote endothelization. However, bioactive coatings on implants have not yet been fully developed for the time-ordered biological requirements of vascular stents. The first month after vascular stent implantation, the pathological changes in the injured vascular tissue are complex and time-ordered. Therefore, vascular stents possess time-dependent biofunctions with early phase anticoagulant and anti-inflammatory properties. In the later stage, inhibitory effects on smooth muscle cell proliferation and the promotion of endothelial cell adhesion might meet the requirements of vascular repair. We fabricated three types of hyaluronic acid nanoparticles (HA-NPs) by subjecting HA and poly(ether imide) to ethyl(dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide coupling reaction. The HA-NPs prepared by HA with a molecular weight of 100 kDa showed the best stability in a hyaluronidase environment. HA-NP composite films (HA-NCFs) were then fabricated by coimmobilizing selected HA-NPs (100 kDa) and HA molecules (100 kDa) through amide reaction on PDA/HD coated 316 L stainless steel surfaces. The detachment behavior of HA-NPs (100 kDa) in PBS for 20 days indicated that the HA-NPs (100 kDa) gradually detached from the surface. In vitro tests (anticoagulant and anti-inflammatory tests, endothelial cells, and smooth muscle cells seeding, and bacterial adhesion test) indicated that the newly fabricated HA-NCFs have inhibitory effects on the adhesion of fibrinogen, platelets, macrophages, bacteria, SMCs, and ECs. As the HA-NPs detached from the surface, the HA-NCFs showed excellent gradual comprehensive biocompatibility, which promoted adhesion and proliferation of ECs while still exerting inhibitory effects on the platelets, macrophages, and SMCs. Finally, in vivo SS wire implantation test (aortic implantation in healthy Sprague-Dawley rats) showed that HA-NCFs possessed anti-inflammatory properties, inhibited the proliferation of smooth muscle cells, and promoted re-endothelialization. In particular, HA-NCFs with time-dependent biofunctions showed better antirestenosis effects than those of surfaces modified with molecular HA, which exhibited constant biocompatibility. This study provides an important basis for the construction of HA-NP composite films with favorable time-dependent biofunctions for the time-ordered biological requirements of vascular stent.

The molecular weights (MWs) of hyaluronic acid (HA) in extracellular matrix secreted from both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) play crucial roles in the cardiovascular physiology, as HA with appropriate MW influences important pathways of cardiovascular homeostasis, inhibits VSMC synthetic phenotype change and proliferation, inhibits platelet activation and aggregation, promotes endothelial monolayer repair and functionalization, and prevents inflammation and atherosclerosis. In this study, HA samples with gradients of MW (4 × 103, 1 × 105, and 5 × 105 Da) were prepared by covalent conjugation to a copolymerized film of polydopamine and hexamethylendiamine (PDA/HD) as multifunctional coatings (PDA/HD-HA) with potential to improve the biocompatibility of cardiovascular biomaterials. The coatings immobilized with high-MW-HA (PDA/HD-HA-2: 1 × 105 Da; PDA/HD-HA-3: 5 × 105 Da) exhibited a remarkable suppression of platelet activation/aggregation and thrombosis under 15 dyn/cm2 blood flow and simultaneously suppressed the adhesion and proliferation of VSMC and the adhesion, activation, and inflammatory cytokine release of macrophages. In particular, PDA/HD-HA-2 significantly enhanced VEC adhesion, proliferation, migration, and functional factors release, as well as the captured number of endothelial progenitor cells under dynamic condition. The in vivo results indicated that the multifunctional surface (PDA/HD-HA-2) created a favorable microenvironment of endothelial monolayer formation and functionalization for promoting reendothelialization and reducing restenosis of cardiovascular biomaterials.

Event Abstract Back to Event Oriented differentiation of MSCs to VECs by FMC assay on the micro-patterned TiO2 nanotubes Jingan Li1, Ping Yang1, Juejue Wu1, Zikun He1, Feng Wu1 and Nan Huang1 1 Southwest Jiaotong University, Key Laboratory for Advanced Technologies of Materials, Ministry of Education, China Introduction: Surface endothelialization of cardivascular implanted biomaterials has been generally accepted as a effective method for the therapy of thrombosis and hyperplasia[1],[2]. Although the VECs of the endothelialization mainly come from the migeration of the neighbor vessels and the capture of EPCs, the MSCs as abundant source should also be considered for endothelialization. Materials and Methods: Fabrication of ECM on the micro-patterned TiO2 nanotubes: The micro-patterned TiO2 nanotubes thin film and ECM loaded micro-patterned TiO2 nanotubes were fabricated as our previous work described[3]. The type IV collagen (CoIV), as the main component of endothelial ECM, was characterized to evaluate the ECM distribution and describe the surface morphology. In brief, all the samples were stained using a FITC labeled antibody (Boshide, China)[4], and then observed under a fluorescence microscopy. The fluorescence images were treated by a Ipwin 32 software, and the 3D images of the surfaces were obtained, subsequently the fluorescence intensity of the FITC on each samples were calculated by the software. The fluorescence intensity of the FITC was positively correlated to the ECM amount[5]. Inducing oriented differentiation of MSCs to VECs by FMC: The human umbilical mesenchymal stem cells (HUMSCs) were isolated from Wharton’s jelly tissue of newborn umbilical cord[6]. The HUMSCs were seeded on each samples with a concentration of 5×104 cells/ml and cultured as a method that was named “Frequently medium change” (FMC). After 2 weeks, the HUMSCs were immunofluorescence stained by the FITC labeled vWF antibody (Sigma, USA) and the nucleus were stained by DAPI (Sigma, USA) to evaluate the differentiation of HUMSC. Results and Discussions: Fig.1 showed that the ECM on the topo-nano, topo and gro-nano distributed more homogeneously compared with ECM on the TiO2 and nano surfaces, suggesting better loading ability of ECM. While the topo-nano showd higher fluorescence intensity of the FITC compared to other samples, which indicated the decreased amounts of ECM in the order: topo-nano> topo> gro-nano > nano> TiO2. Fig. 1 3D images of (A) TiO2, nano, gro-nano, topo, topo-nano surfaces and (B) ECM loaded TiO2, nano, gro-nano, topo, topo-nano surfaces Fig. 2 showed that the cells on the topo-nano surface exhibited positive expression of vWF, implying successful differentiation of HUMSCs to VECs, while the cells on the other surfaces showed negative expression. However, the positive expression of vWF of the HUMSCs on the ECM/topo-nano seemed weak, while this expression might be enhanced by longer FMC culture. Fig.2 Fluorescence images of the induced HUMSCs on all samples stained by FITC labeled antibody of vWF and DAPI Conclusions: In the present work, the endothelial ECM was prepared onto the micro-patterned TiO2 nanotubes for the purpose of inducing the oriented differentiation of HUMSCs to VECs. After the FMC for 2 weeks, the induced HUMSCs on the topo-nano presented positive expression of vWF, which demonstrated successful differentiation preliminarily. This method was anticipated potential application for surface endohelialization of cadiovascular biomaterials. The Key Basic Research Project of China (No. 2011CB606204); The National Natural Science Foundation of China (No. 30870629); China Postdoctoral Science Foundation (2014M562333); Postdoctoral Funds of Southwest jiaotong University (X1101512370435 and YH1101012371444)References:[1] Li GC, Yang P, Qin W, Maitz MF, Zhou S, Huang N. The effect of coimmobilizing heparin and fibronectin on titanium on hemocompatibility and endothelialization. Biomaterials 2011; 32 (21): 4691-4703.[2] Robotti F, Franco D, Bänninger L, Wyler J, Starck CT, Falk V, Poulikakos d, Ferrari A. The influence of surface micro-structure on endothelialization under supraphysiological wall shear stress. Biomaterials 2014; 35 (30): 8479-8486.[3] Wu JJ, Li JA, Wu F, He ZK, Yang P, Huang N. Effect of micropatterned TiO2 nanotubes thin film on the deposition of endothelial extracellular matrix: For the purpose of enhancing surface biocompatibility. Biointerphases 2015; 10: 04A302.[4] Li JA, Zhang K, Wu JJ, Zhang LJ, Yang P, Tu QF, Huang N. Tailoring of the titanium surface by preparing cardiovascular endothelial extracellular matrix layer on the hyaluronic acid micro-pattern for improving biocompatibility. Colloids and Surfaces B: Biointerfaces 2015; 128: 201-210.[5] Li JA, Zhang K, Xu Y, Chen J, Yang P, Zhao YC, Zhao AS, Huang N. A novel coculture model of HUVECs and HUASMCs by hyaluronic acid micropattern on titanium surface. J Biomed Mater Res A 2014; 102: 1950-60.[6] Kestendjieva S, Kyurkchiev D, Tsvetkova G, et al. Characterization of mesenchymal stem cells isolated from the human umbilical cord.Cell Biology International.2008; 32(7):724-32. Keywords: Extracellular Matrix, stem cell, microstructure, endothelialization Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: New Frontier Oral Topic: Biomaterials for cardiovascular applications, vascular grafts and embolic devices Citation: Li J, Yang P, Wu J, He Z, Wu F and Huang N (2016). Oriented differentiation of MSCs to VECs by FMC assay on the micro-patterned TiO2 nanotubes. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.01795 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jingan Li Ping Yang Juejue Wu Zikun He Feng Wu Nan Huang Google Jingan Li Ping Yang Juejue Wu Zikun He Feng Wu Nan Huang Google Scholar Jingan Li Ping Yang Juejue Wu Zikun He Feng Wu Nan Huang PubMed Jingan Li Ping Yang Juejue Wu Zikun He Feng Wu Nan Huang Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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The biocompatibility of cardiovascular devices has always been considered crucial for their clinical efficacy. Therefore, a biofunctional coating composed of Type IV collagen (CoIV) and hyaluronan (HA) was previously fabricated onto the titanium (Ti) substrate for the application of promoting vascular smooth muscle cell contractile phenotype and improving surface endothelialization. However, the anti-inflammation property, blood compatibility and in vivo tissue compatibility of the HA/CoIV coating, as paramount consideration of cardiovascular materials surface coating, have not been investigated. Thus, in this study, the three crucial properties of the HA/CoIV coating were tested. The platelet adhesion/activation test and the dynamic whole blood experiment implied that the HA/CoIV coating had better blood compatibility compared with Ti substrate and pure CoIV coating. The macrophage adhesion/activation and inflammatory cytokine release (tumor necrosis factor-alpha and interleukin-1) results indicated that the HA/CoIV coating could significantly improve the anti-inflammation property of the Ti substrate. The in vivo implantation of SD rats for 3 weeks' results demonstrated that the HA/CoIV coating caused milder tissue response. All these results suggested that the multi-functional HA/CoIV coating possessed good biocompatibility. This research is anticipated to be potentially applied for the surface modification of cardiovascular stents.

Building healthy and oriented smooth muscle cells (SMCs) environment is an effective method for improving the surface endothelialization of the cardiovascular implants. However, a long-term and stable source of SMCs for implantation without immune rejection and inflammation has not been solved, and mesenchymal stem cells (MSCs) differentiation may be a good choice. In this work, two types of TiO2 micro/nano interfaces were fabricated on titanium surface by photolithography and anodic oxidation. These TiO2 micro/nano interfaces were used to regulate the differentiation of the MSCs. The X-ray diffraction (XRD) detection showed that the TiO2 micro/nano interfaces possessed the anatase crystal structure, suggesting good cytocompatibility. The CCK-8 results indicated the TiO2 micro/nano interfaces improved MSC proliferation, further immunofluorescence staining and calculation of the cell morphology index proved the micro/nano surfaces also elongated MSCs and regulated MSCs oriented growth. The specific staining of α-SMA, CNN-1, vWF, CD44 and CD133 markers revealed that the micro/nano surfaces induced MSCs differentiation to contractile SMCs, and the endothelial cells (ECs) culture experiment indicated that the MSCs induced by micro/nano interfaces contributed to the ECs attachment and proliferation. This method will be further studied and applied for the surface modification of the cardiovascular implants.

Surface modification by conjugating biomolecules has been widely proved to enhance biocompatibility of cardiovascular implanted devices. Here, we aimed at developing a multifunctional surface that not only provides good hemocompatibility but also functions well in inducing desirable vascular cell-material interaction. In the present work, the multicoatings of hyaluronic acid (HA) and dopamine (PDA) were prepared onto 316L stainless steel (316L SS) via chemical conjugation (Michael addition, Schiff base reaction, and electrostatic adsorption). The results of platelet adhesion and activation and the whole blood tests indicated that the HA/PDA coatings obtained better hemocompatibility compared with the bare 316L SS and HA or PDA immobilized on 316L SS. The HA/PDA coatings also inhibited the proliferation of smooth muscle cells and adhesion/activation of macrophages effectively, whereas not all the HA/PDA coatings improved surface endothelialization rapidly and the effects of the multifunctional coatings on endothelial cell growth depend on the HA amounts (1.0, 2.0, and 5.0 mg/mL, labeled as PDA-HA-1, PDA-HA-2, and PDA-HA-5 respectively). Herein the PDA-HA-1 and PDA-HA-2 coatings were found to improve endothelial cell adhesion and proliferation significantly. The tissue compatibility of the HA/PDA coatings also depends on the HA amounts, and the PDA-HA-2 coating was proved to cause milder in vivo tissue response. Additionally, the mechanism of the HA molecular weight change and in vivo tissue response was also explored. These results effectively suggested that the HA/PDA coating might be promising when serving as a cardiovascular implanted device coating.

The vascular endothelial cells (EC) extracellular matrix (ECM) on the biomaterial surface can significantly improve the blood compatibility and cell compatibility of the cardiovascular materials. In the present study, two types of micropatterned TiO2 nanotubes surfaces (gronano and toponano) were fabricated on the titanium surface by photolithography and two-step anodizing technology, for the purpose of enhancing the deposition and loading ability of the EC ECM. The effect of the micropatterned nanotubes on EC ECM deposition and loading was investigated by qualitative and quantitative characterizations of type IV collagen (CoIV). The blood compatibility of the deposited ECM layers was evaluated by platelet adhesion and activation tests, and the endothelialization function of the deposited ECM layers was investigated by EC culture for 3 days. As a result, there was more CoIV on the toponano surface compared with the control. Meanwhile, the ECM loaded toponano (ECM/toponano) possessed better blood compatibility and better endothelialization than the control. This ECM loaded micro-/nanocomposite thin film was anticipated for the potential application of the surface modification of cardiovascular devices based on its excellent biocompatibility.