Water-Triggered Segment Orientation of Long-Lasting Anti-Biofouling Polyurethane Coatings on Biomedical Catheters via Solvent Exchange Strategy.

The formation of biofilm and thrombus on medical catheters poses a significant life-threatening concern. Hydrophilic anti-biofouling coatings upon catheter surfaces with complex shapes and narrow lumens are demonstrated to have the potential in reducing complications. However, their effectiveness is constrained by poor mechanical stability and weak substrate adhesion. Herein, a novel zwitterionic polyurethane (SUPU) with strong mechanical stability and long-term anti-biofouling is developed by controlling the ratio of sulfobetaine-diol and ureido-pyrimidinone. Once immersed in water, as-synthesized zwitterionic coating (SUPU3 SE) would undergo a water-driven segment reorientation to obtain much higher durability than its direct drying one, even under various extreme treatments, including acidic solution, abrasion, ultrasonication, flushing, and shearing, in PBS at 37 °C for 14 days. Moreover, SUPU3 SE coating could achieve a 97.1% of exceptional reducing protein fouling, complete prevention of cell adhesion, and long-lasting anti-biofilm performance even after 30 days. Finally, the good anti-thrombogenic formations of SUPU3 SE coating with bacterial treatment are validated in blood circulation through an ex vivo rabbit arteriovenous shunt model. This work provides a facile approach to fabricating stable hydrophilic coating through a simple solvent exchange to reduce thrombosis and infection of biomedical catheters.

Thermal and Reactive Oxygen Species Dual-Responsive OEGylated Polysulfides with Oxidation-Tunable Lower Critical Solution Temperatures.

In this work, two monomethoxy oligo(ethylene glycol) (OEG)-substituted episulfides are prepared and a series of polysulfides are synthesized with subsequent ring-opening polymerization. The OEGylated polysulfides exhibit thermal and reactive oxygen species (ROS) dual-responsive behavior. Their lower critical solution temperatures (LCSTs) are close to human body temperature and depend on the degree of polymerization and OEG length. Notably, the LCST of the polysulfide increases linearly with the oxidation degree by H2 O2 , showing a highly tunable change regulated by the ratio between hydrophobic sulfide and hydrophilic sulfoxide/sulfone in the backbone. Further, the OEGylated polysulfide can act as a ROS scavenger to protect red blood cells (RBCs) from oxidative damage in an RBCs aging model in vitro. This work paves a facile way to synthesize LCST-tunable polysulfides, which hold great promise in biological applications.

Facile Fabrication of Hierarchically Thermoresponsive Binary Polymer Pattern for Controlled Cell Adhesion.

A versatile platform allowing capture and detection of normal and dysfunctional cells on the same patterned surface is important for accessing the cellular mechanism, developing diagnostic assays, and implementing therapy. Here, an original and effective method for fabricating binary polymer brushes pattern is developed for controlled cell adhesion. The binary polymer brushes pattern, composed of poly(N-isopropylacrylamide) (PNIPAAm) and poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) chains, is simply obtained via a combination of surface-initiated photopolymerization and surface-activated free radical polymerization. This method is unique in that it does not utilize any protecting groups or procedures of backfilling with immobilized initiator. It is demonstrated that the precise and well-defined binary polymer patterns with high resolution are fabricated using this facile method. PNIPAAm chains capture and release cells by thermoresponsiveness, while POEGMA chains possess high capability to capture dysfunctional cells specifically, inducing a switch of normal red blood cells (RBCs) arrays to hemolytic RBCs arrays on the pattern with temperature. This novel platform composed of binary polymer brush pattern is smart and versatile, which opens up pathways to potential applications as microsensors, biochips, and bioassays.

Hierarchical Polymer Brushes with Dominant Antibacterial Mechanisms Switching from Bactericidal to Bacteria Repellent.

Although polycationic surfaces have high antimicrobial efficacies, they suffer from high toxicity to mammalian cells and severe surface accumulation of dead bacteria. For the first time, we propose a surface-initiated photoiniferter-mediated polymerization (SI-PIMP) strategy of constructing a "cleaning" zwitterionic outer layer on a polycationic bactericidal background layer to physically hinder the availability of polycationic moieties for mammalian cells in aqueous service. In dry conditions, the polycationic layer exerts the contact-active bactericidal property toward the adherent bacteria, as the zwitterionic layer collapses. In aqueous environment, the zwitterionic layer forms a hydration layer to significantly inhibit the attachment of planktonic bacteria and the accumulation of dead bacteria, while the polycationic layer kills bacteria occasionally deposited on the surface, thus preserving the antibacterial capability for a long period. More importantly, the zwitterionic hydrated layer protects the mammalian cells from toxicity induced by the bactericidal background layer, and therefore hierarchical antibacterial surfaces present much better biocompatibility than that of the naked cationic references. The dominant antibacterial mechanism of the hierarchical surfaces can switch from the bactericidal efficacy in dry storage to the bacteria repellent capability in aqueous service, showing great advantages in the infection-resistant applications.

Plasma proteins adsorption mechanism on polyethylene-grafted poly(ethylene glycol) surface by quartz crystal microbalance with dissipation.

Protein adsorption has a vital role in biomaterial surface science because it is directly related to the hemocompatibility of blood-contacting materials. In this study, monomethoxy poly(ethylene glycol) (mPEG) with two different molecular weights was grafted on polyethylene as a model to elucidate the adsorption mechanisms of plasma protein through quartz crystal microbalance with dissipation (QCM-D). Combined with data from platelet adhesion, whole blood clotting time, and hemolysis rate, the blood compatibility of PE-g-mPEG film was found to have significantly improved. Two adsorption schemes were developed for real-time monitoring of protein adsorption. Results showed that the preadsorbed bovine serum albumin (BSA) on the surfaces of PE-g-mPEG films could effectively inhibit subsequent adsorption of fibrinogen (Fib). Nonspecific protein adsorption of BSA was determined by surface coverage, not by the chain length of PEG. Dense PEG brush could release more trapped water molecules to resist BSA adsorption. Moreover, the preadsorbed Fib could be gradually displaced by high-concentration BSA. However, the adsorption and displacement of Fib was determined by surface hydrophilicity.

Tunable backbone-degradable robust tissue adhesives via in situ radical ring-opening polymerization.

Adhesives with both robust adhesion and tunable degradability are clinically and ecologically vital, but their fabrication remains a formidable challenge. Here we propose an in situ radical ring-opening polymerization (rROP) strategy to design a backbone-degradable robust adhesive (BDRA) in physiological environment. The hydrophobic cyclic ketene acetal and hydrophilic acrylate monomer mixture of the BDRA precursor allows it to effectively wet and penetrate substrates, subsequently forming a deep covalently interpenetrating network with a degradable backbone via redox-initiated in situ rROP. The resulting BDRAs show good adhesion strength on diverse materials and tissues (e.g., wet bone >16 MPa, and porcine skin >150 kPa), higher than that of commercial cyanoacrylate superglue (~4 MPa and 56 kPa). Moreover, the BDRAs have enhanced tunable degradability, mechanical modulus (100 kPa-10 GPa) and setting time (seconds-hours), and have good biocompatibility in vitro and in vivo. This family of BDRAs expands the scope of medical adhesive applications and offers an easy and environmentally friendly approach for engineering.

Reduction of thrombotic and inflammatory complications of polystyrene-block-polyisoprene-block-polystyrene (SIS) with one-step electrospinning.

Polystyrene-block-polyisoprene-block-polystyrene (SIS) has been used as biomaterials due to its soft and stable properties under physiological conditions. However, the thrombotic and inflammatory complications caused by SIS restrain its application as blood-contacting implant. To overcome this problem, the hydrophilic core-shell structured SIS-based microfiber with antioxidant encapsulation is fabricated with one-step reactive electrospinning. We demonstrate that the phase separation of SIS and acylated Pluronic F127 (F127-DA) components and crosslinking during electrospinning renders the microfiber blood compatible and stable under physiological condition; the encapsulation of 2-O-d-glucopyranosyl-l-ascorbic acid (AA-2G) in microfiber and subsequent release of AA-2G detoxifies the excess reactive oxygen species (ROS). The microfibers are nontoxic to cells and promote the fast growth and proliferation of human umbilical vein endothelial cells (HUVECs) in the presence of ROS; the thrombotic and inflammatory complications are effectively reduced with implant evaluation in vivo. Therefore, our work paves a new way to improve the biocompatibility of SIS, making it a promising candidate for blood contact materials.

Poly(γ-glutamic acid)-based electrospun nanofibrous mats with photodynamic therapy for effectively combating wound infection.

Pathogenic bacterial infections associated with wound healing progress usually result in serious complications. Herein, biocompatible and antimicrobial electrospun nanofibrous mats with photodynamic therapy (PDT) effect were fabricated to accelerate the infected wound healing. The nanofibrous mats were fabricated by co-electrospining of polyanionic poly(γ-glutamic acid) (γ-PGA) and cationic photosensitizer 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin tetra (p-toluenesulfonate) (TMPyP) in aqueous solution and stabilized by the chemical crosslinking. The as-prepared nanofibrous mats can not only confer the moist microenvironment to the wound bed, but also provide potent bactericidal activity upon visible light irradiation by releasing the cytotoxic reactive oxygen species (ROS). The antibacterial assay in vitro showed that they can effectively eradicate the board-spectrum bacteria at a relatively low loading dose of TMPyP (e.g., 0.1 wt%). Meanwhile, those nanofibrous mats showed good biocompatibility with no obvious adverse effects on mammalian cells and red blood cells (RBCs). The animal test in vivo suggested that the restrained inflammatory reaction and better wound healing could be achieved upon timely and effective antibacterial treatment with negligible local toxicities. This biocompatible and antibacterial γ-PGA-TMPyP nanofibrous mat may show great potential in practical infection-resistant applications, particularly for wound dressing applications.

A dynamic remodeling bio-mimic extracellular matrix to reduce thrombotic and inflammatory complications of vascular implants.

Thrombotic and inflammatory complications induced by vascular implants remain a challenge to treat cardiovascular disease due to the lack of self-adaption and functional integrity of implants. Inspired by the dynamic remodeling of the extracellular matrix (ECM), we constructed a bio-mimic ECM with a dual-layer nano-architecture on the implant surface to render the surface adaptive to inflammatory stimuli and remodelable possessing long-term anti-inflammatory and anti-thrombotic capability. The inner layer consists of PCL-PEG-PCL [triblock copolymer of polyethylene glycol and poly(ε-caprolactone)]/Au-heparin electrospun fibers encapsulated with indomethacin while the outer layer is composed of polyvinyl alcohol (PVA) and ROS-responsive poly(2-(4-((2,6-dimethoxy-4-methylphenoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (PBA) fibers. In response to acute inflammation after vascular injury, the outer layer reduces ROS rapidly by PBA degradation for inflammation suppression. The degraded outer layer facilitates inner layer reconstruction with enhanced hemocompatibility through the H-bond between PVA and PCL-PEG-PCL. Furthermore, chronic inflammation is effectively depressed with the sustained release of indomethacin from the inner layer. The substantial enhancement of the functional integrity of implants and reduction of thrombotic and inflammatory complications with the self-adaptive ECM are demonstrated both in vitro and in vivo. Our work paves a new way to develop long-term anti-thrombotic and anti-inflammatory implants with self-adaption and self-regulation properties.

Biomimicking Dual-Responsive Extracellular Matrix Restoring Extracellular Balance through the Na/K-ATPase Pathway.

Biomedical implant mimicking the physiological extracellular matrix (ECM) is a new strategy to modulate the cell microenvironment to improve implant integrity and longevity. However, the biomimicking ECM suffers from low sensitivity to pathological change and low efficiency to restore the physiological state in vivo. To overcome these problems, reactive oxygen species (ROS) and K+ dual-responsive micro-/nanofibers that encapsulate ascorbic acid-2-glucoside (AA-2G) are fabricated on an elastomer substrate with electrospinning to mimic the ECM. The strategy is based on the fact that ROS and K+ dual responsiveness enhance the sensitivity of the ECM to pathological changes and delivery of AA-2G from the ECM to cell membrane promotes reactivating Na/K-ATPase and shifting cellular diseased conditions to the normal state. We demonstrate that the ROS and K+-responsive tripolymer of poly(ethylene glycol)diacrylate, 1,2-ethanedithiol, and 4-nitrobenzo-18-crown-6-ether (PEGDA-EDT-BCAm) are synthesized successfully; the ECM composed of acylated poly(caprolactone)/PEGDA-EDT-BCAm/AA-2G micro-/nanofibers is prepared through reactive electrospinning; the ECM is sensitive to ROS and K+ concentration in the microenvironment to release AA-2G, which targets the membrane to remove the excessive ROS and reactivate Na/K-ATPase; as a result, the ECM reduces oxidative stress and restores the extracellular physiological state both in vitro and in vivo. This work provides basic principles to design an implant that can adjust the extracellular microenvironment while avoiding pathogenicity to improve implant integrity and longevity in vivo.

Water-Insoluble Polymeric Guanidine Derivative and Application in the Preparation of Antibacterial Coating of Catheter.

Antibacterial coatings have been considered as an effective method for preventing the implant-associated infections caused by the bacterial colonization. In this study, we report a water-insoluble polyelectrolyte-surfactant complex, poly(hexamethylene biguanide) hydrochloride-sodium stearate (PHMB-SS) that can be facilely coated onto the surfaces of biomedical catheter and kill the bacteria by releasing the PHMB and prevent the generation of the biofilm. The PHMB-SS-coated surfaces showed better bactericidal activity toward Staphylococcus aureus and Escherichia coli. The PHMB-SS-coated catheters could not only relatively prevent the bacterial colonization in vitro but also in an implant-associated bacterial infection animal model in vivo. Moreover, no significant cytotoxicity and host response were observed in vitro and in vivo, indicating the high biocompatibility of the coating. The water-insoluble antibacterial coating reported in this work represents a novel approach to build a simple and effective coating for the prevention of device-associated infections.

A hierarchical polymer brush coating with dual-function antibacterial capability.

Bacterial infections are problematic in many healthcare-associated devices. Antibacterial surfaces integrating the strength of bacteria repellent and bactericidal functions exhibit an encouraging efficacy in tackling this problem. Herein, a hierarchical dual-function antibacterial polymer brush coating that integrates an antifouling bottom layer with a bactericidal top layer is facilely constructed via living photograft polymerization. Excellent resistance to bacterial attachment is correlated with the antifouling components, and good bactericidal activity is afforded by the bactericidal components, and therefore the hierarchical coating shows an excellent long-term antibacterial capability. In addition, due to the presence of the hydrophilic background layer, the hierarchical surface has the greatly improved biocompatibility, as shown by the suppression of platelet adhesion and activation, the inhibition of erythrocyte adhesion and damage, and low toxicity against mammalian cells. The hierarchical polymer brush system provides the basis for the development of long-term antibacterial and biocompatible surfaces.

A hierarchical polymer brush coating with dual-function antibacterial capability.

Bacterial infections are problematic in many healthcare-associated devices. Antibacterial surfaces integrating the strength of bacteria repellent and bactericidal functions exhibit an encouraging efficacy in tackling this problem. Herein, a hierarchical dual-function antibacterial polymer brush coating that integrates an antifouling bottom layer with a bactericidal top layer is facilely constructed via living photograft polymerization. Excellent resistance to bacterial attachment is correlated with the antifouling components, and good bactericidal activity is afforded by the bactericidal components, and therefore the hierarchical coating shows an excellent long-term antibacterial capability. In addition, due to the presence of the hydrophilic background layer, the hierarchical surface has the greatly improved biocompatibility, as shown by the suppression of platelet adhesion and activation, the inhibition of erythrocyte adhesion and damage, and low toxicity against mammalian cells. The hierarchical polymer brush system provides the basis for the development of long-term antibacterial and biocompatible surfaces.

Bioinspired Antioxidant Defense System Constructed by Antioxidants-Eluting Electrospun F127-Based Fibers.

Cells were continuously exposed to oxidative damage by overproduction of reactive oxygen species (ROS) when they contacted implanted biomaterials. The strategy to prevent cells from oxidative injures remains a challenge. Inspired by the antioxidant defense system of cells, we constructed a biocompatible and ROS-responsive architecture on the substrate of styrene-b-(ethylene-co-butylene)-b-styrene elastomer (SEBS). The strategy was based on fabrication of architectures through reactive electrospinning of mixture including SEBS, acylated Pluronic F127, copolymer of poly(ethylene glycol) diacrylate and 1,2-ethanedithiol (PEGDA-EDT), and antioxidants (AA-2G) and ROS-triggered release of AA-2G from microfibers to detoxify the excess ROS. We demonstrated that the stable and hydrophilic architecture was constructed by phase separation of SEBS/F127 components and cross-linking between polymer chains during electrospinning; the ROS-responsive fibers controlled the release of AA-2G and the interaction of AA-2G with ROS reduced the oxidative damage to cells. The bioinspired architecture not only reduced mechanical and oxidative damage to cells but also maintained normal ROS level for physiological hemostasis. This work provides basic principles to design and develop antioxidative biomaterials for implantation in vivo.

Temperature-Responsive Hierarchical Polymer Brushes Switching from Bactericidal to Cell Repellency.

Unlike conventional poly(N-isopropylacrylamide) (PNIPAM)-based surfaces switching from bactericidal activity to bacterial repellency upon decreasing temperature, we developed a hierarchical polymer architecture, which could maintain bactericidal activities at room temperature while presenting bacterial repellency at physiological temperature. In this architecture, a thermoresponsive bactericidal upper layer consisting of PNIPAM-based copolymer and vancomycin (Van) moieties was built on an antifouling poly(sulfobetaine methacrylate) (PSBMA) bottom layer via sequential surface-initiated photoiniferter-mediated polymerization. At room temperature below the lower critical solution temperature (LCST), the PNIPAM-based upper layer was stretchable, facilitating contact killing of bacteria by Van. At physiological temperature (above the LCST), the PNIPAM-based layer collapsed, thus leading to the burial of Van and exposure of bottom PSBMA brushes, finally displaying notable performances in bacterial inhibition, dead bacteria detachment, and biocompatibility, simultaneously. Our strategy provides a novel pathway in the rational design of temperature-sensitive switchable surfaces, which shows great advantages in the real-world infection-resistant applications.

Liquid-Infused Poly(styrene-b-isobutylene-b-styrene) Microfiber Coating Prevents Bacterial Attachment and Thrombosis.

Infection and thrombosis associated with medical implants cause significant morbidity and mortality worldwide. As we know, current technologies to prevent infection and thrombosis may cause severe side effects. To overcome these complications without using antimicrobial and anticoagulant drugs, we attempt to prepare a liquid-infused poly(styrene-b-isobutylene-b-styrene) (SIBS) microfiber coating, which can be directly coated onto medical devices. Notably, the SIBS microfiber was fabricated through solution blow spinning. Compared to electrospinning, the solution blow spinning method is faster and less expensive, and it is easy to spray fibers onto different targets. The lubricating liquids then wick into and strongly adhere the microfiber coating. These slippery coatings can effectively suppress blood cell adhesion, reduce hemolysis, and inhibit blood coagulation in vitro. In addition, Pseudomonas aeruginosa (P. aeruginosa) on the lubricant infused coatings slides readily, and no visible residue is left after tilting. We furthermore confirm that the lubricants have no effects on bacterial growth. The slippery coatings are also not cytotoxic to L929 cells. This liquid-infused SIBS microfiber coating could reduce the infection and thrombosis of medical devices, thus benefiting human health.

Nonleaching Bacteria-Responsive Antibacterial Surface Based on a Unique Hierarchical Architecture.

Bacteria-responsive surfaces popularly exert their smart antibacterial activities by bacteria-triggered delivery of antibacterial agents; however, the antibacterial agents should be additionally reloaded for the renewal of these surfaces. Herein, a reversible, nonleaching bacteria-responsive antibacterial surface is prepared by taking advantage of a hierarchical polymer brush architecture. In this hierarchical surface, a pH-responsive poly(methacrylic acid) (PMAA) outer layer serves as an actuator modulating the surface behavior on demand, while antimicrobial peptides (AMP) are covalently immobilized on the inner layer. The PMAA hydration layer renders the hierarchical surface resistant to initial bacterial attachment and biocompatible under physiological conditions. When bacteria colonize the surface, the bacteria-triggered acidification allows the outermost PMAA chains to collapse, therefore exposing the underlying bactericidal AMP to on-demand kill bacteria. In addition, the dead bacteria can be released once the PMAA chains resume their hydrophilicity because of the environmental pH increase. The functionality of the nonleaching surface is reversible without additional reloading of the antibacterial agents. This approach provides a new methodology for the development of smart surfaces in a variety of practical biomedical applications.

Toughening polylactide with polyether-block-amide and thermoplastic starch acetate: Influence of starch esterification degree.

Native corn starch was esterified with acetic anhydride and plasticized with glycerol to give the thermoplastic starch acetate (TPSA). TPSA was blended with polylactide (PLA) and polyether-block-amide-graft-glycidyl methacrylate (PEBA-g-GMA) to obtain biodegradable PLA/PEBA-g-GMA/TPSA blends with high notched impact resistance and low cost. Compared with PLA/PEBA-g-GMA blends, as much as 9 wt% expensive PEBA-g-GMA elastomer could be substituted by the slightly acetylated thermoplastic starch while retaining high impact strength. The mechanical properties depended on the esterification degree of starch acetate. The impact strength, tensile strength and elongation at break increased to the peak value with increasing the esterification degree from 0 to 0.04, thereafter they decreased on further increasing the esterification degree. The morphological results showed that the TPSA particles were smaller and more uniform at the optimum esterification degree of 0.04, leading to the peak value of the mechanical properties.

Effect of grafted PEG chain conformation on albumin and lysozyme adsorption: A combined study using QCM-D and DPI.

In this study, elucidation of protein adsorption mechanism is performed using dual polarization interferometry (DPI) and quartz crystal microbalance with dissipation (QCM-D) to study adsorption behaviors of bovine serum albumin (BSA) and lysozyme (LYZ) on poly (ethylene glycol) (PEG) layers. From the analysis of DPI, PEG2000 and PEG5000 show tight and loose mushroom conformations, respectively. Small amount of LYZ could displace the interfacial water surrounding the tight mushroomed PEG2000 chains by hydrogen bond attraction, leading to protein adsorption. The loose mushroomed PEG5000 chains exhibit a more flexible conformation and high elastic repulsion energy that could prevent protein adsorption of all BSA and most of LYZ. From the analysis of QCM, PEG2000 and PEG5000 show tight and extended brush conformations. The LYZ adsorbed mass has critical regions of PEG2000 (0.19 chain/nm(2)) and PEG5000 (0.16 chain/nm(2)) graft density. When graft density of PEG is higher than the critical region (brush conformations), the attraction of hydrogen bonds between PEG and LYZ is the dominant factor. When graft density of PEG is lower than the critical region (mushroom conformations), elastic repulsion between PEG and proteins is driven by the high conformation entropy of PEG chains, which is the dominant force of steric repulsion in PEG-protein systems. Therefore, the adsorption of BSA is suppressed by the high elastic repulsion energy of PEG chains, whereas the adsorption of LYZ is balanced by the interactions between the repulsion of entropy elasticity and the attraction of hydrogen bonds.

Binary release of ascorbic acid and lecithin from core-shell nanofibers on blood-contacting surface for reducing long-term hemolysis of erythrocyte.

There is an urgent need to develop blood-contacting biomaterials with long-term anti-hemolytic capability. To obtain such biomaterials, we coaxially electrospin [ascorbic acid (AA) and lecithin]/poly (ethylene oxide) (PEO) core-shell nanofibers onto the surface of styrene-b-(ethylene-co-butylene)-b-styrene elastomer (SEBS) that has been grafted with poly (ethylene glycol) (PEG) chains. Our strategy is based on that the grafted layers of PEG render the surface hydrophilic to reduce the mechanical injure to red blood cells (RBCs) while the AA and lecithin released from nanofibers on blood-contacting surface can actively interact with RBCs to decrease the oxidative damage to RBCs. We demonstrate that (AA and lecithin)/PEO core-shell structured nanofibers have been fabricated on the PEG grafted surface. The binary release of AA and lecithin in the distilled water is in a controlled manner and lasts for almost 5 days; during RBCs preservation, AA acts as an antioxidant and lecithin as a lipid supplier to the membrane of erythrocytes, resulting in low mechanical fragility and hemolysis of RBCs, as well as high deformability of stored RBCs. Our work thus makes a new approach to fabricate blood-contacting biomaterials with the capability of long-term anti-hemolysis.