An endothelium membrane mimetic antithrombotic coating enables safer and longer extracorporeal membrane oxygenation application.

Thrombosis and plasma leakage are two of the most frequent dysfunctions of polypropylene (PP) hollow fiber membrane (PPM) used in extracorporeal membrane oxygenation (ECMO) therapy. In this study, a superhydrophilic endothelial membrane mimetic coating (SEMMC) was constructed on polydopamine-polyethyleneimine pre-coated surfaces of the PPM oxygenator and its ECMO circuit to explore safer and more sustainable ECMO strategy. The SEMMC is fabricated by multi-point anchoring of a phosphorylcholine and carboxyl side chained copolymer (PMPCC) and grafting of heparin (Hep) to form PMPCC-Hep interface, which endows the membrane superior hemocompatibility and anticoagulation performances. Furthermore, the modified PPM reduces protein adsorption amount to less than 30 ng/cm2. More significantly, the PMPCC-Hep coated ECMO system extends the anti-leakage and non-clotting oxygenation period to more than 15 h in anticoagulant-free animal extracorporeal circulation, much better than the bare and conventional Hep coated ECMO systems with severe clots and plasma leakage in 4 h and 8 h, respectively. This SEMMC strategy of grafting bioactive heparin onto bioinert zwitterionic copolymer interface has great potential in developing safer and longer anticoagulant-free ECMO systems. STATEMENT OF SIGNIFICANCE: A superhydrophilic endothelial membrane mimetic coating was constructed on surfaces of polypropylene hollow fiber membrane (PPM) oxygenator and its ECMO circuit by multi-point anchoring of a phosphorylcholine and carboxyl side chain copolymer (PMPCC) and grafting of heparin (Hep). The strong antifouling nature of the PMPCC-Hep coating resists the adsorption of plasma bio-molecules, resulting in enhanced hemocompatibility and anti-leakage ability. The grafted heparin on the zwitterionic PMPCC interface exhibits superior anticoagulation property. More significantly, the PMPCC-Hep coating achieves an extracorporeal circulation in a pig model for at least 15 h without any systemic anticoagulant. This endothelial membrane mimetic anticoagulation strategy shows great potential for the development of safer and longer anticoagulant-free ECMO systems.

Achieving superior anticoagulation of endothelial membrane mimetic coating by heparin grafting at zwitterionic biocompatible interfaces.

Thrombosis and bleeding are common complications of blood-contacting medical device therapies. In this work, an endothelium membrane mimetic coating (PMPCC/Hep) has been created to address these challenges. The coating is fabricated by multi-point anchoring of a phosphorylcholine copolymer (poly-MPC-co-MSA, PMPCC) with carboxylic side chains and end-group grafting of unfractionated heparin (Hep) onto polydopamine precoated blood-contacting material surfaces. The PMPCC coating forms an ultrathin cell outer membrane mimetic layer to resist protein adsorption and platelet adhesion. The tiny defects/pores of the PMPCC layer provide entrances for heparin end-group to be inserted and grafted onto the sub-layer amino groups. The combination of the PMPCC cell membrane mimetic anti-fouling nature with the grafted heparin bioactivity further enhances the anticoagulation performance of the formed endothelium membrane mimetic PMPCC/Hep coating. Compared to conventional Hep coating, the PMPCC/Hep coating further decreases protein adsorption and platelet adhesion by 50 % and 90 %, respectively. More significantly, the PMPCC/Hep coating shows a superior anticoagulation activity, even significantly higher than that of an end-point-attached heparin coating. Furthermore, the blood coagulation function is well preserved in the PMPCC/Hep coating anticoagulation strategy. All the results support that the PMPCC/Hep coating strategy has great potential in developing more efficient and safer blood-contacting medical devices.

Tumor microenvironment-responsive polydopamine-based core/shell nanoplatform for synergetic theranostics.

Theranostic agents that integrate diagnostic and therapeutic modalities have drawn extensive attention due to their ability to deliver real-time imaging-guided tumor treatment. Herein, a novel core-shell polydopamine (PDA)-based theranostic agent (PDA@TA-Fe) was fabricated via a two-step strategy. Upon 808 nm and 1064 nm laser irradiation, this agent exhibited high photothermal conversion efficiencies of 29% and 41%, respectively. After endocytosis into tumor cells, the TA-Fe shell of PDA@TA-Fe gradually disintegrated in the weakly acidic tumor microenvironment (TME), and released the TA as an acidity-activated reductant that could reduce Fe3+ to Fe2+. Subsequently, the generated Fe2+ reacted with H2O2 to generate toxic hydroxyl radicals (˙OH) via the Fenton reaction, which induced the apoptosis of tumor cells and achieved the chemodynamic therapy (CDT). The heat produced by photothermal therapy (PTT) accelerated the ˙OH generation to achieve a synergetic effect of CDT/PTT. In vivo tumor-xenograft imaging and therapeutic assays demonstrated obvious contrast enhancement at the tumor site in the T1/T2-weighted MR imaging and efficient tumor suppression achieved after the intravenous injection of this agent because of the enhanced permeation and retention (EPR) effect. This study offered a new strategy to design an "all-in-one" nanoplatform for T1/T2 MR imaging-guided synergistic cancer treatment of CDT/PTT.

Effects of Non-native Interactions on Frustrated Proteins Folding under Confinement.

In vitro, kinetically significant non-native interactions have been identified experimentally during the folding of proteins Im7, Im9, and A39V/N53P/V55L Fyn SH3 domain. To understand the role of non-native interactions on the folding of some frustrated proteins in chaperone, we employed native-centric models with and without additional transferable, sequence-dependent non-native hydrophobic interactions to comparatively study the folding behaviors of the three proteins confined in spherical cages. Under purely repulsive confinement, as a decrease of cavity size, the non-native interactions increase, especially in the unfolded state, enhancing the roughness of the folding energy landscape. As a result, the increase in native stability for the three proteins by the model incorporated non-native interactions (db + MJ hϕ model) is much smaller than that by the purely native-centric model (desolvation-barrier (db) model); the acceleration of folding simulated by the db + MJ hϕ model is much slower than that via the db model; in particular, the folding rate of Im7 decreases when reducing the cavity size under zero-denaturant condition. The repulsive confinement can also promote formation of specific non-native contacts in the transition state and favor more folding pathways passing through the misfolded state, leading to a higher population of the misfolded intermediate. In an attractive cage, the attractive interactions could inhibit the formation of intrachain non-native contacts and provide alternate folding pathways to the native state so that the population of the misfolded intermediate decreases when increasing the strength of attractive interaction between the substrate protein and cavity wall. This study should be helpful in general to understand how the chaperonins reshape the folding energy landscape of some frustrated proteins.

Mechanistic Investigation of a Dual Bicyclic Photoinitiating System for Synthesis of Organic-Inorganic Hybrid Materials.

One-pot synthesis of organic-inorganic hybrid materials under light requires specific photoinitiating systems which are able to release several different initiating species after light absorption. In this paper, the reaction mechanism of a photocyclic three-component initiating system based on isopropylthioxanthone as photoinitiator and an iodonium salt and a thiol as co-initiators was studied. It is shown that this system enables simultaneous release of both radicals and protons which are able to initiate a free radical photopolymerization and the hydrolysis-condensation of a sol-gel network, respectively. Time-resolved investigations by laser flash photolysis show that the initiating species are produced within two concomitant cyclic reaction mechanisms depending on the relative quantities of the co-initiators. Protons resulting from the secondary dark reaction of the photocyclic systems are detected at the microsecond scale by means of a proton-sensitive molecular probe, and corresponding quantum yields are measured. Finally, synthesis of organic, inorganic, and hybrid materials under LED light at 395 nm is evaluated with respect to the mechanistic considerations demonstrating the dual initiating character of the system.

Substrate independent coating formation and anti-biofouling performance improvement of mussel inspired polydopamine.

Mussel inspired polydopamine (PDA) coating has been proven to be a simple and effective method for surface modification of biomaterials. However, the adhesive functional groups remaining on the surface of PDA coating may promote the attachment of nonspecific proteins and microorganisms and hinder anti-biofouling performance. In this study, the PDA coating formation process is monitored in real-time by a sensitive surface plasmon resonance (SPR) technique at different pH values, initial dopamine concentrations and deposition times. The coating morphology is observed by atomic force microscopy (AFM). Nonspecific protein adsorption, platelet and fibroblast cell adhesion, as well as bacteria attachment on the PDA coatings of different thicknesses are measured to evaluate their anti-biofouling performance. Thickness-dependent biofouling of the PDA coatings is demonstrated by the accumulation of adhesive functional groups within the PDA matrix. In order to reduce the biofouling, we treat the PDA coating by FeCl3 coordination, NaIO4 oxidation, heating in air and grafting with a phosphorylcholine copolymer bearing active ester groups. The modified surfaces are characterized by X-ray photoelectron spectroscopy (XPS) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy measurements. Interestingly, all the treatments help to resist protein adsorption significantly. More excitingly, the simple grafting strategy with a phosphorylcholine copolymer can resist more than 99% of platelet, fibroblast, and bacteria cell attachment, 98% of bovine serum albumin and 95% of bovine plasma fibrinogen adsorption on the PDA coating. These results may find applications in the vast area of surface antifouling, especially for most biomedical devices.

Surface reconstruction and hemocompatibility improvement of a phosphorylcholine end-capped poly(butylene succinate) coating.

Control over cell-material surface interactions is the key to many new and improved biomedical devices. In this study, we present a simple yet effective surface modification method that allows for the surface reconstruction and formation of cell outer membrane mimetic structure on coatings that have significantly increased hemocompatibility. To achieve this, a phosphorylcholine end-capped poly(butylene succinate) (PBS-PC) was synthesized and dip-coated on coverslips. The surface structure of the amphiphilic PBS-PC film was reconstructed by heating in a vacuum oven to obtain the less hydrophilic surface and by immersing in hot water to obtain the more hydrophilic surface. Significant changes in the surface element concentration were observed by X-ray photoelectron spectroscopy analysis and changes in surface wettability were measured by sensitive dynamic contact angle technique. Scanning electron microscope images showed different morphologies of the reconstructed surfaces. Interestingly, the reconstruction between the less hydrophilic and more hydrophilic surfaces is reversible. More importantly, both the reconstructed surfaces are stable in room condition for more than 6 months, and both the surfaces show significant improvement in hemocompatibility as revealed by protein adsorption and platelet adhesion measurements. This reversible surface reconstruction strategy and the interesting results may be significant for fabricating stable and hemocompatible surfaces on differently shaped biomedical devices.

Synthesis and characterization of polymerizable one-component photoinitiator based on sesamol.

Migration stability and biocompatibility are the crucial features for a photoinitiator or coinitiator used in UV curable formulations, especially when the cured product is in direct contact with food or human skin. To reduce the migration issues and increase the biocompatibility, a polymerizable one-component photoinitiator, 1-(1,3-benzodioxol-5-yloxy)-3-(4-benzoylphenoxy)propan-2-yl acrylate (BDOBPAc), based on sesamol and benzophenone has been synthesized. The photopolymerization induced by BDOBPAc was monitored by real-time infrared spectroscopy. The rate of decomposition and the migration stability of photoinitiators were studied by UV-Vis spectroscopy. The results showed that BDOBPAc is an effective free radical photoinitiator with good migration stability, which has great potential to be widely used in the food packing or biomedical fields.

Synthesis and photopolymerization kinetics of benzophenone sesamol one-component photoinitiator.

A benzodioxole derivative, 4-(2-(benzodioxol-5-yloxy)ethoxy)benzophenone (BPC2BDO), based on 4-hydroxybenzophenone and sesamol was synthesized, and used as a one-component Type II photoinitiator. The structure of BPC2BDO was characterized by elementary analysis, APCI-MS, (1)H NMR, and (13)C NMR. The rate of decomposition (R(d)) of BPC2BDO in acetonitrile was studied by UV-Vis spectroscopy and found that R(d) was proportional to light intensity. Real-time near-IR was used to study the kinetics of photopolymerization of the photoinitiator. As the benzophenone (BP) moiety and hydrogen donor were introduced into one molecule in BPC2BDO, radicals could be generated through intra-molecular reaction due to the close vicinity of the hydrogen donor and BP, which might be faster than inter-molecular reaction. The results also showed that the rate of polymerization of acrylates was significantly higher than that of methacrylates at the same polymerization conditions; the functionality of acrylates, concentration of BPC2BDO, and light intensity affected the polymerization rate and the final conversion.

Influence of structure of benzodioxole derivatives on photoinitiation efficiency of benzophenone.

To investigate the influence of the substituents at the 5-position of the phenyl ring of benzodioxole on the reactivity of a benzophenone (BP)/benzodioxole-based photoinitiator system, three benzodioxole-based compounds were synthesized in this study. The structure was characterized by FT-IR, (1)H NMR and (13)C NMR. The kinetics were monitored by a real-time Fourier Transform near-IR (FT-NIR) spectrometer. The results showed that the introduction of the electron-donating substituents in the 5-position of the phenyl ring contributed to the increase in the reactivity of the BP/benzodioxole-based system. On the contrary, the electron-drawn substituents at the 5-position of the phenyl ring caused the opposite effect. Compared with the BP/ethyldimethylaminobenzoate (EDAB) photoinitiating system, the combination of BP/5-methoxy-1,3-benzodioxole (BDOOMe) led to almost the same R(p(max)) and final double bond conversions. It indicated that BDOOMe had the potential to be used as a coinitiator in the place of an amine in current BP/amine initiating systems for practical applications to decrease cytotoxicity and yellowing.

Photopolymerized water-soluble chitosan-based hydrogel as potential use in tissue engineering.

Novel biodegradable hydrogels by photocrosslinking macromers based on chitosan derivative are reported. Photocrosslinkable macromers, a water-soluble (methacryloyloxy) ethyl carboxyethyl chitosan were prepared by Michael-addition reaction between chitosan and ethylene glycol acrylate methacrylate. The macromers were characterized by Fourier transform infrared spectroscopy, (1)H NMR and (13)C NMR. Hydrogels were fabricated by exposing aqueous solutions of macromers with 0.1% (w/v) photoinitiator to UV light irradiation, and their swelling kinetics as well as degradation behaviors was evaluated. The results demonstrated that the degradation rates were affected strongly by crosslinking density. The hydrogel was compatible to Vero cells, not exhibiting significant cytotoxicity. Cell culture assay also demonstrated that the hydrogels were good in promoting the cell attachment and proliferation, showing their potential as tissue engineering scaffolds.

Influence of chemical structures of benzodioxole-based coinitiators on the properties of the unfilled dental resin.

To investigate the influence of chemical structures of benzodioxole-based coinitiator on the initiating reactivity and the mechanical properties of cured samples for the unfilled dental resin, a mixture of 2,2-bis[4-(2-hydroxy-3-methacryloxyprop-1-oxy)phenyl]propane (bis-GMA) and triethylene glycol dimethacrylate (TEGDMA) (70/30 wt.%) was photoinduced by combinations of camphorquinone (CQ) and benzodioxole derivatives. 2-(N,N-Dimethylamino)ethyl methacrylate (DMEM) was used as control. The kinetics was monitored by a real-time Fourier transformation infrared spectroscopy (FTIR) and the dynamic mechanical analysis was performed on a dynamic mechanical analyzer (DMA). The cytotoxicity property of the cured samples was evaluated by MTT assay in vitro using VERO as reference cell lines. The results indicated that the 4-position phenyl ring substituents of the benzodioxole-based coinitiator had great influence on the initiating reactivity. Incorporating substituents with pi electron acceptors in the 4-position of phenyl ring led to the decrease of the rate of polymerization (R(p)) of the CQ/benzodioxole derivatives. However, the electron-donating substituents were useful to increase the reactivity. When compared with CQ/amine initiating systems, the combination of CQ and benzodioxole compounds caused lower R(p) but the comparable final double bond conversion. All the cured films initiated by CQ/benzodioxole derivatives had almost the same glass transition temperature (T(g)) and storage modulus. Indirect cytotoxicity assessment indicated low cytotoxicity of benzodioxole derivatives. These results were very useful for the design of benzodioxole derivatives with satisfactory reactivity and biocompatibility, and are very important for clinical applications.

Dimethacrylate based on cycloaliphatic epoxide for dental composite.

OBJECTIVES: The aim of this study was to investigate the kinetics and mechanical properties of dimethacrylate monomer based on cycloaliphatic epoxide for dental restorative composite. METHODS: Dimethacrylate based on cycloaliphatic epoxide (EPCDMA) was copolymeirzed with TEGDMA by varying the curing conditions: monomer composition and light intensity. A real-time near FTIR technique was employed to monitor the double bond conversion and the rate of polymerization. Dynamic mechanical analysis was performed on a dynamic mechanical analyzer, and volume shrinkage of the cured samples was determined by pycnometric method. RESULTS: The results of kinetics showed that, two peaks of maximum rate of polymerization (Rpmax) occurred when the amount of TEGDMA was more than 30wt%. Increasing the amount of TEGDMA, the final double bond conversion and polymerization shrinkage both increased, while the glass transition temperature (Tg) decreased. All EPCDMA/TEGDMA mixtures had slightly higher storage modulus at body temperature (37 degrees C). When compared with Bis-GMA/TEGDMA (70/30), the EPCDMA/TEGDMA (70/30) system assumed similar reactivity and volume shrinkage but higher Tg. SIGNIFICANCE: EPCDMA had comparable mechanical properties to those of Bis-GMA.

Benzodioxole derivative as coinitiator for dental resin.

OBJECTIVE: The aim of this work was to examine whether it was possible to substitute benzodioxole derivatives for amine as coinitiators for dental application. MATERIAL AND METHODS: A mixture of urethane dimethacrylate (UDMA)/triethylene glycol dimethacrylate (TEGDMA) (70/30 wt%), camphorquinone (CQ) and coinitiators was photocured. Real time Fourier Transform Infrared Spectroscopy with a horizontal sample holder was used to monitor the extent of polymerization. Dynamic mechanical analysis was performed over a temperature range from -50 degrees C to 200(o)C, with a ramping rate of 5(o)C per minute, using extension mode. RESULTS: Benzodioxole derivatives as coinitiator improved the rate of polymerization and final double bond conversion of the dental resin. The cured samples showed similar properties, e.g. modulus, glass transition temperature, water sorption and solubility. CONCLUSION: The results indicate that two benzodioxole derivatives, piperonyl alcohol (PAL) and benzodioxole (BDO), are viable alternatives to conventional amines as coinitiator. The biocompatibility of benzodioxole derivatives makes them more promising than amine in dental resin formulations.

Investigation of 3,4-methylenedioxybenzene methoxyl methacrylate as coinitiator and comonomer for dental application.

In this study, 3,4-methylenedioxybenzene methoxyl methacrylate (MDBMM) was synthesized for the purpose of replacing both triethylene glycol dimethacrylate (TEGDMA) and tertiary amine, which was usually used as a comonomer and coinitiator for dental resin, respectively. Urethane dimethacrylate (UDMA) was chosen as a monomer. Real time near Fourier transform infrared (FTIR) with a horizontal sample holder and dynamic mechanical analyzer (DMA) were used to study the kinetics and mechanical properties, respectively. The results showed that the addition of MDBMM as a coinitiator in UDMA/TEGDMA/CQ (70/30/0.5 wt %) system led to the increase of the rate of polymerization. When compared with the commercial polymerizable amine, 2-(N,N-dimethyl amino)ethyl methacrylate (DMEM), MDBMM showed comparable initiating reactivity and led to higher modulus around human body temperature (37 degrees C). MDBMM as a comonomer resulted in slightly higher final double bond conversion than that of TEGDMA, which brought higher modulus around 37 degrees C. Therefore, MDBMM can be used as both potential coinitiator and comonomer for dental application.

A natural component as coinitiator for unfilled dental resin composites.

A natural component, 1,3-benzodioxole (BDO), was used for the purpose of replacing the conventional amine for dental composite. Camphorquinone (CQ)/BDO was used to initiate the photopolymerization of urethane dimethacrylate (UDMA)/triethylene glycol dimethacrylate (TEGDMA) (70/30 wt %). The kinetics was recorded by real-time Fourier transformation infrared spectroscopy (FTIR). The mechanical properties were measured by dynamic mechanical analyzer (DMA), and CQ/ethyl 4-N,N-dimethylaminobenzoate (EDMAB) mixture was used as control in the same photocuring condition. The results indicated that, the addition of BDO as coinitiator greatly improved the rate of polymerization and final double bond conversion (DC), when compared with the system initiated by CQ alone. BDO and EDMAB were found to reach almost the same final DC (75%), though the kinetics of two systems was different. Comparing with EDMAB, BDO brought approximately the same glass transition temperature (Tg), but slightly higher storage modulus around 37 degrees C. The water sorption and solubility for two mixtures were almost the same and within the range of the ISO 4049's standards. These results suggested that BDO was an effective alternative to conventional amine for coinitiator. And the human diet characteristics of BDO made it more promising than amine in the dental resin formulations.