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Antifouling Zwitterionic Polymer Coatings for Blood-Bearing Medical Devices
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  • Kagya Amoako
    Kagya Amoako
    Department of Chemistry and Chemical and Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States
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    Orcidhttps://orcid.org/0000-0002-2150-5214
  • Rei Ukita
    Rei Ukita
    Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37240, United States
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  • Keith E. Cook*
    Keith E. Cook
    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
    *[email protected]
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    Orcidhttps://orcid.org/0000-0002-5604-3718
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Cite this: Langmuir 2025, 41, 5, 2994–3006
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https://doi.org/10.1021/acs.langmuir.4c04532
Published January 27, 2025

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Abstract

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Blood-bearing medical devices are essential for the delivery of critical care medicine and are often required to function for weeks to months. However, thrombus formation on their surfaces can lead to reduced device function and failure and expose patients to systemic thrombosis risks. While clinical anticoagulants reduce device related thrombosis, they also increase patient bleeding risk. The root cause of device thrombosis and inflammation is protein adsorption on the biomaterial surfaces of these devices. Protein adsorption activates the coagulation cascade and complement, and this, in turn, activates platelets and white blood cells. Surface modifications with zwitterionic polymers are particularly effective at reducing protein adsorption as well as conformational changes in proteins due to their hydrophilicity. Multiple coating strategies have been developed using carboxybetaine (CB), sulfobetaine (SB), and 2-methacryloyloxyethyl phosphorylcholine (MPC) zwitterionic polymers applied to the metals and hydrophobic polymers that make up the bulk of blood-bearing medical devices. These coatings have been highly successful at creating large reductions in protein adsorption and platelet adhesion during studies on the order of hours on flat surfaces and at reducing thrombus formation for up to a few days in full medical devices. Future work needs to focus on their ability to limit inflammation, particularly during hemodialysis, and in providing anticoagulation on the order of weeks, particularly in artificial lungs.

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Published as part of Langmuir special issue “2025 Pioneers in Applied and Fundamental Interfacial Chemistry: Shaoyi Jiang”.

Introduction

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Blood coagulation has, historically, been the most significant challenge in creating safe and effective blood-bearing medical devices. The development and use of vascular grafts and artificial heart valves, kidneys, hearts, and lungs have all been plagued by pathogenic blood clot formation. (1,2) Coagulation occludes blood passages through the device, increasing blood flow resistance, covering key components, and ultimately, damaging the key functions of the medical device. Vascular grafts occlude and reduce tissue perfusion; dialyzers and artificial lungs lose their mass transfer function; and blood pumps shoot thromboemboli into the vasculature, causing downstream, native organ dysfunction or failure.
Historically, most of the solutions that have been employed to overcome clot formation in these devices have been only slightly better than the problem itself. The traditional method of combating clot formation is to deliver intravenous heparin to provide systemic anticoagulation. Heparin is inexpensive and effective at inhibiting the common coagulation cascade by increasing antithrombin III’s (ATII) inhibition of Factor Xa (FXa) and thrombin. Unfortunately, by inhibiting the common pathway of the coagulation cascade, it equally inhibits clot formation caused by artificial surfaces, driven by the intrinsic branch of the coagulation cascade, and clot formation in patient tissues, driven by the extrinsic branch. As a result, heparin creates a marked increase in bleeding risk that can create a similar, life-threatening risk as the coagulation itself. (3,4) Numerous other systemic anticoagulants have been developed, (5−13) and while there is hope for selective intrinsic branch anticoagulants, (6,7,12−14) there is currently no commercial anticoagulant that selectively and potently inhibits the medical device and not the patient.
Initial attempts to selectively anticoagulate medical devices focused on ionically- and covalently bound heparin coatings. The goal of ionically bound heparin was to slowly leach heparin from the surface to focus coagulation in the device. Any benefit this (7) provided, however, was short-lived. The goal of covalently bound heparin was to tether the heparin at the surface using long-chain spacer polymers, enabling long-term, continued inactivation of FXa and thrombin only within the device. These coatings were able to reduce protein adsorption and clot formation only over short periods (<6 h). (15,16) However, further study demonstrated that the bound heparin had a marked decrease in its ability to bind ATIII and inhibit FXa and thrombin and that the key advantage of these coatings was actually their ability to decrease adsorption of proteins that initiate and accelerate coagulation. (17)
As a result, research began to focus on inhibiting protein adsorption on the surfaces of these devices via surface grafting of albumin, polyethylene glycol (PEG), and zwitterionic polymers, including 2-Methacryloyloxyethyl phosphorylcholine (MPC), polysulfobetaine (PSB), and polycarboxybetaine (PCB). Of these coatings, zwitterionic materials quickly proved to be the most effective at limiting protein adsorption from blood due to their ultrahydrophilic nature. Research over the past 15 years has proven that these materials are effective at limiting nonspecific protein adsorption from blood, and current work focuses on demonstrating and optimizing that effectiveness from periods of days to weeks to months in a variety of medical devices.

Protein Adsorption and Blood Activation in Medical Devices

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Most blood bearing medical devices are constructed from hydrophobic polymers such as polycarbonate, polyurethane, polypropylene, polydimethylsiloxane, and polytetrafluoroethylene. A smaller subset, primarily ventricular assist devices, are constructed from titanium and stainless steel. Each of these materials rapidly adsorbs proteins from blood. While numerous proteins are adsorbed, a few have an outsized impact on device function due to their ability to activate coagulation and inflammation. Adsorption of FXII initiates a conformational change and activation to Factor XIIa. (18−20) Factor XIIa (FXIIa) then initiates the intrinsic branch of the coagulation cascade, leading to activation of the common coagulation cascade and formation of solid clot (Figure 1). Surface adsorption of fibrinogen also induces a conformational change, (21) enabling platelets to bind to fibrinogen via their Gp IIb/IIIa receptors, which activate them to release their numerous procoagulants and further accelerate the coagulation process.

Figure 1

Figure 1. Clot formation in blood bearing medical devices: A) the large internal surface area of an oxygenator and its tubing fouled with blood clot; B) and C) clots on blood pumps; and D) and E) stopcocks and connectors occluded by blood clot.

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Protein adsorption also can lead to activation of leukocytes and inflammation. Factor XII adsorption activates the intrinsic branch of the coagulation cascade, forming FXIIa and kallikrein, and complement adsorption leads to the formation of complement fragments C3a, C4a, and C5a. (22−25) These factors, in turn, activate neutrophils, monocytes, basophils, and mast cells. In high surface area systems, such as cardiopulmonary bypass, extracorporeal membrane oxygenation, and kidney dialysis, this can cause a systemic inflammatory response that is broadly damaging to major organs.
Coagulation and inflammation, and their negative consequences, could be markedly reduced in blood bearing medical devices if protein adsorption could be reduced. The focus of surface coating research over the last 30 years has, therefore, focused on surface grafting of long chain molecules that form polymer networks or dense, brush-like structures to resist protein adsorption. These coatings include polyethylene glycol (PEG), oligoethylene glycol (OEG), Poly 2-Methacryloyloxyethyl phosphorylcholine (pMPC), polysulfobetaine methacrylate (pSBMA), and polycarboxybetaine methacrylate (pCBMA). While PEG and OEG proved effective at generating mild decreases in protein adsorption, they are less hydrophilic than the zwitterionic coatings, break down relatively quickly, and elicit an immune response. (26,27) This makes them poorly suited for use in long-term blood-bearing medical device applications, where coatings are most needed. Thus, this review will focus on zwitterionic surface coatings due to their greater hydrophilicity, resistance to protein adsorption, and longevity.

Zwitterionic Coating Structure and Function

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The structures of pSBMA, pMPC, and pCBMA are shown in Figure 2. Each polymer has a set of common structural and chemical characteristics: (1) each features a backbone of repeating polymer segments that is anchored to the substrate through a variety of linkers, (2) each segment has a polar, zwitterionic side group, and (3) the separation between the side groups tends to be short. Zwitterions are the key to these coatings’ antifouling and anticoagulant properties. The positively charged amine groups, paired with the negatively charged carboxyl, sulfonate, and phosphate groups, define the polar, zwitterionic nature of the side groups. This polarity promotes hydration through electrostatic interaction with water. To generate effective antifouling, the substrate is coated with high packing densities of the zwitterionic polymer. If sufficiently dense, when the medical device is primed with an aqueous solution (saline, lactated Ringer’s solution, etc.), the water occupies the spaces between the zwitterionic groups. This creates a dense hydration layer over the device’s surfaces that repulses proteins. When the coated surface contacts blood, proteins such as FXIIa and fibrinogen would thus need to displace the water to reach the hydrophobic surface, adsorb, and initiate their procoagulant functions. Therefore, to be an effective coating, the substrate must have sufficient packing density to generate a tightly bound hydration layer that effectively serves as an energetic barrier that proteins need to overcome.

Figure 2

Figure 2. Select zwitterion side groups used as hydrophilic coatings.

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The ability of any of these coatings to resist fouling is dependent on their chain lengths. Longer chain lengths promote a thicker hydration layer, enhancing the material’s resistance to nonspecific protein adsorption while shorter chain lengths provide a thinner hydration layer, which may be less effective in preventing fouling. However, graft density can be higher with shorter chains due to reduced steric hindrance when compared to longer chains. Further, hemodynamic stresses may impact longer chain grafts more negatively as they can get entangled while shorter chains will exhibit less mechanical instability. Ultimately, the optimal chain length of zwitterionic grafts is one that favors thicker, denser hydration layers with excellent mechanical stability. (28−31)

Coating Methods

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The most commonly coated medical device materials are polydimethylsiloxane (PDMS), polyurethane (PU), polycarbonate, polymethylpentene (PMP), titanium, and stainless steel. As these surfaces are generally inert to direct modification, they require some preprocessing before the coating process can be initiated. For polymeric materials, the preprocessing may involve plasma exposure, etching, etc. to cleave the bonds in the polymer chains that are at the surface for (1) initiator attachment for the purpose of graft-from coating or (2) functional group attachment for the purpose of graft-to coating. If the substrate is metallic, then other mechanisms for functionalizing the metal surface for subsequent grafting can be applied after surface cleaning. Surface grafting, dip-coating, and spray coating are typical methods employed for polymeric surfaces while vapor deposition, electrophoretic deposition, surface grafting, sol–gel coating, and dip-coating are generally applied to metals. A summary of all the methods is included in Table 1, but chemical vapor deposition, self-assembled monolayers (SAM), dip coating, and surface grafting have been particularly useful in coating blood bearing devices composed of either polymeric or metallic surfaces.
Table 1. Blood Bearing Device Coating Methods
Coating MethodsBrief Description
Grafting (Graft to and Graft from)Grafting to Involves attaching preformed hydrophilic polymers to the device surface.
Grafting from Initiates polymerization directly from the device surface, growing polymer chains in situ.
Self-Assembled MonolayersHydrophilic molecules are adsorbed onto the device surface, forming a monolayer through spontaneous self-assembly driven by chemical affinity.
PhotopolymerizationA light-sensitive hydrophilic monomer is polymerized onto the device surface using UV or visible light, creating a cross-linked hydrophilic coating.
Sol–Gel CoatingInvolves the transition of a solution system from a liquid “sol” into a solid “gel” phase, resulting in a uniform hydrophilic coating after drying and curing.
Physical Vapor DepositionSputtering: This technique involves ejecting material from a target to coat a substrate, creating thin, uniform coatings.
Evaporation: Material is vaporized and then condensed onto the medical device surface, forming a coating.
Chemical Vapor DepositionThis process involves reacting gaseous precursors at elevated temperatures to form a solid material on the device surface, resulting in a durable and uniform coating.
Dip CoatingThe device is immersed in a hydrophilic polymer solution and then withdrawn at a controlled rate, allowing a thin film to form on the surface. The coating is then dried and cured.
Spray CoatingA hydrophilic material is sprayed onto the device surface, creating a uniform coating.
Spin CoatingA small amount of coating solution is applied to the center of the device, which is then spun at high speed to spread the solution uniformly by centrifugal force.
Layer-by-Layer (LbL) AssemblyThis technique involves sequentially dipping the device in oppositely charged polyelectrolyte solutions, building up multilayered hydrophilic coatings.
Plasma PolymerizationPlasma is used to polymerize monomers directly onto the device surface, forming thin hydrophilic coatings with good adhesion and uniformity.
Electrophoretic DepositionHydrophilic particles suspended in a liquid medium are deposited onto the device surface under the influence of an electric field.
Self-Segregating PDMSPMDS devices are constructed from a dilute mixture of PDMS-zwitterion copolymers and PDMS, and the copolymers self-segregate to the aqueous surface.
The chemical vapor deposition (CVD) coating process deposits gaseous precursors of the coating material onto the substrate (e.g., cardiovascular stents with titanium nitride coatings), typically at high temperatures. The substrate is exposed to one or more volatile precursors (tert-butyl peroxide, a chain growth monomer, silane or tetraethylorthosilicate) that react and decompose on the surface, forming a solid, thin film for further functionalization. Substrates like poly(styrene) (PS), poly(ethylene terephlate) (PET), or silicon treated with a phenyl silane coupling agent contains an aromatic group, and the precursor oxidant FeCl3 can be utilized to create surface radicals from which a step growth polymerization of a conducting polymer brush can proceed. It can deposit uniform, conformal coatings even on complex shapes, and thin, dense films with excellent adhesion are achievable. However, due to the high temperature requirement, temperature sensitive materials are not suitable. Additionally, CVD requires expensive equipment. (32−35)
The dip-coating process involves immersing a device (e.g., catheters) into a coating solution and then withdrawing it at a controlled speed to deposit a thin film of the coating material. The thickness depends on the withdrawal speed and solution properties. This method is simple and cost-effective, scalable for large batches, and good for applying uniform thin films on regular surfaces. However, it is limited to simpler geometries, coating thickness can vary with irregular surfaces, and postprocessing is often needed for curing or drying. (36,37)
A SAM forms when molecules spontaneously organize themselves into a single, ordered layer on a surface, typically by chemisorption. (38,39) It is relatively easy to prepare and forms a well-defined coating with specific functional groups. For example, oxide substrates (e.g., metal stents or ventricular assist devices) can be “SAMed” with silanes and electrode sensors with thiols. (40) SBMA can then be covalently attached to the silane “SAMed” surface following the exposure of the surface to bromoisobutyryl bromide solution at room temperature.
Surface grafting involves attaching molecules, including large polymers, to the surface of a device. This can be done through chemical reactions (e.g., grafting-from or grafting-to) or by initiators. In the graft-from approach, polymer chains are grown directly from the surface itself. This is achieved by first attaching initiators or active sites on the surface, and then using these initiators to start polymerization reactions in which monomers are added to these active sites, and polymer chains are grown outward from the surface. In the graft-to process, preformed chains are attached to substrates. Plasma treatment is often a precursor to surface coating and further modification steps for stabilization and functionalization are also applied after coating. Artificial lungs, (7,41−44) vascular grafts, (45−51) and catheters (52−55) have been modified using this method.
Recently, researchers have investigated generating a zwitterionic coating on PDMS via the bulk polymer itself. (56,57) In brief, small amounts (<2 wt %) of PDMS-zwitterion copolymers are incorporated within the PDMS during manufacture. The copolymers then spontaneously self-segregate to surfaces in contact with aqueous solutions, thus effectively coating the outer PDMS surface with a zwitterionic layer to resist nonspecific adsorption. The potential benefit of this approach is eliminating the coating step when manufacturing PDMS devices, such as PDMS microfluidics.
The optimal choice for a coating method is likely dependent on the blood-bearing medical device material; whether the surface requires maintenance of diffusive or convective mass transfer; and whether the surface is a part of a complex, three-dimensional medical device. As discussed previously, CVD is more appropriate for metals, due to its high temperatures. Devices that facilitate mass transport may require dip-coating or surface grafting, depending on the geometric complexity of the blood contacting surfaces. Mass transport is a critical factor for the function of artificial lungs, dialyzers, and electrode sensors. Artificial lungs must maintain efficient gas diffusion; dialyzers must maintain effective convective and/or diffusive fluid and waste removal during hemodialysis; and glucose sensors with implantable electrodes must maintain effective glucose diffusion. As such, coating methods that apply thin films (10–50 nm) with high permeability are likely required. Dip-coating works better on sensors due to their simplicity while the wash-through coating methods are optimal for coating whole, internal flow devices like artificial lungs and dialyzers. In contrast, ventricular assist devices, catheters, and vascular grafts do not have mass transfer or high surface permeability requirements and can, therefore, be modified with thicker coatings to achieve greater durability, resistance to fouling, and if needed, drug release.
As an example, the Jiang group developed a lightly cross-linked polycarboxybetaine hydrogel coating (Figure 3) to a glucose sensor using dip coating. This coating allowed glucose to diffuse through the hydrogel matrix, enabling accurate glucose measurement, while the coating inhibited sensor fouling to maintain accurate measurement while in whole blood contact for 42 days. (58) Similar materials have since been applied to glucose sensors to improve their signal-to-noise ratio. (59) Similarly, the Jiang and Cook groups developed a wash-through, graft-from coating method (7,41,43,44) for artificial lungs due to the geometric complexity of the device as well as the need to maintain efficient gas exchange. This method used adhesive polydopamine (pDOPA) to graft pCBMA and pSBMA to the entire interior of artificial lungs (Figure 4). This coating process maintains a thin coating (<50 nm) to maintain gas transfer efficiency, is capable of coating multiple types of hydrophobic polymers, and reduces protein adsorption by greater than 90%. (41,43)

Figure 3

Figure 3. A) Schematic illustration of (left to right) a low-fouling conventional hydrogel showing protein entrapment and adhesion; a polymer brush surface coating, which highly resists nonspecific protein adsorption; and a low-fouling, lightly cross-linked hydrogel, which allows the free movement of proteins in and out of the hydrogel matrix without nonspecific protein adsorption. B) Preparation process of a glucose sensor coated with a pCBMA hydrogel lightly cross-linked with a CBMA cross-linker (CBMAX) and loaded with covalently immobilized GOx, leading to high GOx loading density, high glucose detection sensitivity, and very low nonspecific protein adsorption. C) Comparison of the experimental glucose sensor coated with 0.1% polyCBMA hydrogel with the Medtronic sensor in whole blood taken from rats, showing the blood glucose level is accurately measured by the uncoated, commercial sensor for less than 2 days and by the coated sensor for 42 days. D) Comparison of sensor sensitivity: blood glucose level is plotted as a function of PBS dilution. TMSPMA: 3-(trimethoxysilyl)propyl methacrylate. NHS/EDC: N-hydroxysuccinimide/1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. GOx: glucose oxidase. Adapted with permission from ref (58). Copyright 2012 Biomaterials.

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Figure 4

Figure 4. Achieving surface-focused anticoagulation in oxygenators using surface grafting with antifouling zwitterions conjugated with dopamine adhesive linkers. A) Coating of oxygenator fibers with dopamine-zwitterion (DOPA-zwitter) grafts using a wash through approach. B) Dopamine-polycarboxybetaine methacrylate (DOPA-pCBMA) and C) Dopamine-polysulfobetaine methacrylate (DOPA-pSBMA) were synthesized via solution atomic transfer radical polymerization. The reaction sequence starts with the reaction of dopamine (DOPA) linker with 2-bromoisobutyl bromide (Br-i-Bu-Br) initiator to form DOPA-Br and then the reaction of DOPA-Br with polycarboxybetaine methacrylate (CBMA) or polysulfobetaine methacrylate (SBMA) for form DOPA-pCBMA or DOPA-pSBMA. The substrate’s surface modification with DOPA-pCB polymer via pseudo one step “graft-to” coating approach was then applied. 1:6 free DOPA to DOPA-pCB were blended into a 2.5 mg/mL in tris(hydroxymethyl)aminomethane (TRIS) buffer (pH = 8.5) and was used to bathe substrates for 6 h.

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Performance of Zwitterionic Coatings on Flat Surfaces

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Development of zwitterionic surface coatings has typically progressed from initial testing under simplified, idealized conditions to more complex, realistic conditions. Accordingly, initial evaluation of nonspecific protein adsorption on pSB- and pCB- SAMs occurred on gold and glass surfaces under static incubation from single protein solutions. In this setting, protein adsorption was (<3 ng/cm2) as measured by surface plasmon resonance sensors. (26−28) Similar results were then observed when these coatings were exposed to 100% blood plasma. When pSB was grafted to the NH2-terminated substrate at pH 8.5 by the SAM approach, the coating surface had undetectable adsorption from single-protein solutions (<1 mg mL–1 fibrinogen or lysozyme in PBS) and effectively resisted protein adsorption from 100% plasma and serum, allowing only 8 ± 7 and 22.5 ± 7.5 ng/cm2, respectively. Thereafter, graft-from DOPA-pCBMA was applied to PDMS membranes, which were then tested under the more realistic and challenging setting of flowing, citrated, platelet rich plasma. In this setting the DOPA-pCBMA coating reduced platelet binding by 77%. (41)
A summary of the antifouling levels (Table 2) exhibited by different types of zwitterionic coatings on model surfaces can be considered as somewhat of a benchmark of surface modification of blood bearing medical devices for antifouling. Carboxybetaine, sulfobetaine, and phosphorylcholine coatings can reduce protein adsorption to levels of less than 5, 10, and 10 ng/cm2, respectively. However, the test setting of these benchmarks does not reflect that of the complex test environments of coated blood-bearing devices which include different substrate materials, complex 3D structures and fluid mechanics, and whole blood interaction with the surface. (30−34)
Table 2. Antifouling Activity Levels of Zwitterionic Polymer Coating Type (29,60−63)
Coating TypeProtein Adsorption (ng/cm2) 100% blood plasma
Carboxybetaine<5
Sulfobetaine<10
Phosphorylcholine<10
Due to their antiadsorptive function, zwitterionic coatings are also resistant to bacterial adhesion and are expected to be able to reduce inflammation. P. aeruginosa bacterial density on graft-to pCB coated glass surfaces was less than 7% of that on the glass surface at 15 h of incubation. Additionally, grafting of DOPA-pSBMA polymers to glass led to a 99.6% reduction in bacterial adhesion after 2 days when compared to an uncoated control. (64) Lastly, zwitterionic coatings should, in theory, be able to reduce systemic inflammation by reducing adsorption and activation of the contact system of the coagulation cascade and complement activation from plasma. Unfortunately, this has not yet been studied directly. Indirect evidence of the reduction of inflammation can, however, be found in studies demonstrating a reduction in capsule formation for at least 3 months after subcutaneous implantation of pCBMA and polyhydroxyethyl methacrylate hydrogel disks in pockets made on either side of the central dorsal surface (65) in mice and reduction of the inflammatory response to neural implants after 1 week in mouse brains. (66)

Performance of Zwitterionic Coatings on Full Devices

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Evaluation of thrombosis on three-dimensional surfaces is more complex, and less commonly reported than the two-dimensional flat sheet evaluation. Flat sheets are simpler surfaces to manipulate and to achieve complete surface coverage with zwitterionic polymers. However, these types of surfaces are idealized and rarely seen in actual blood-bearing medical devices. In fact, medical device surface geometries run the gamut from a simple tubular geometry in catheters all the way to complex, packed beds of hollow fiber membranes in oxygenators and dialyzers. Thus, coating these devices is more challenging because coating solutions do not effectively wet surfaces that are deep within a packed bed or overlapping with other surfaces. Furthermore, the blood flow velocity and patterns vary widely in these devices, ranging from low-shear, creeping flow in mass exchangers to high-shear, potentially turbulent flow in blood pumps.

Catheters

Catheters such as peripheral venous and central venous lines and Swan-Ganz catheters are tubes with one or more lumens intended for blood sampling and pressure measurements. The most common materials used in this application include polyvinyl chloride, silicone, and polyurethane. (67) Clinically, catheters are first inserted peripherally into patient’s vasculature, and for longer catheters like central venous lines and Swan-Ganz, their tips are advanced centrally closer toward the heart. Central venous catheters are commonly used during critical care monitoring and cancer treatments; however, their prolonged duration of use is associated with increased risks of thrombosis and bloodstream infection. In the United States, there are over 30,000 central line associated bloodstream infections each year in intensive care and acute care facilities. (68) These occur in spite of antibacterial and antiseptic materials that may be coated or impregnated on catheter surfaces, such as silver, minocycline, rifampicin, and chlorohexidine. While these coated catheters have shown to reduce the risks of bloodstream infections relative to uncoated in clinical settings, (69) these do not directly or indirectly inhibit thrombosis. Catheter thrombosis is less commonly reported but can occur and propagate to more serious clot complications like deep vein thrombosis. (70,71) Zwitterionic surface coatings may therefore address both of these biological problems simultaneously by reducing nonspecific adsorption and adhesion of clotting factors, platelets, and microbes.
Clinically, there are no zwitterion-coated catheters on the market, but MPC and PSB coatings have been tested on central venous catheters in vitro and in animal models. Smith and colleagues coated polyurethane catheter surfaces with pSBMA in a graft-from approach, demonstrating a greater than 99% reduction in thrombus formation vs uncoated catheters over 4 h of in vivo testing and greater than 97% reduction in adhesion of a multiple bacterial strains after 24 h of incubation. (55) Researchers have also combined zwitterionic coatings with surface nitric oxide (NO) release to enhance antimicrobial and antithrombotic effects. Nitric oxide is a signaling molecule released by the endothelium for various purposes, including short-acting platelet inhibition, and by macrophages as an antibacterial agent. This approach was first examined by the Cook and Jiang groups on flat sheets, demonstrating synergistic benefits at reducing platelet binding. (41) Hitesh Handa and his research group then developed a multilayer catheter consisting of MPC graft-to topcoats that cover the outer and inner surfaces of the catheter, with an NO-releasing layer sandwiched in between. (54) This combination achieved a nearly two-log reduction in bacteria colony forming units vs uncoated catheters and reduced visual thrombus formation after a 7-day jugular implantation study in rabbits. Furthermore, the combination of NO and zwitterionic coating was superior to either alone. Hou et al. from Nanyang Technological University also developed a diblock copolymer brush structure consisting of an NO donor moiety and pSBMA anchored to a polyurethane surface using a graft-from approach. (52) Their catheter was tested in a five-day porcine model, demonstrating more than a four-log reduction in biofilm formation compared to a pristine catheter. Li et al. from Sichuan University is also developing a multimodal coating that consists of copper, lysine, and pSBMA that are grafted to the polyurethane catheter surface using DOPA. (53) Catechol-copper coordination strengthens the coating’s adhesion to surfaces and reduces the risk of coating disintegration. Furthermore, copper catalyzes the reaction of endogenous nitric oxide donor species to release nitric oxide and is also inherently an antimicrobial metal species. Lysine further stabilizes polydopamine synthesis and also naturally has strong affinity to fibrinolytic proteins including plasminogen. The combination approach achieved over 98% reduction in clot weight in both a 1-h rabbit arteriovenous vascular shunt model and a 7-day rat jugular vein implant model.

Vascular Grafts

Vascular grafts are artificial blood vessels commonly used to replace or to bypass the dysfunctional native vessels. Synthetic vascular grafts are most commonly made of polytetrafluoroethylene (PTFE), polyester (i.e., Dacron), and polyurethane. Occlusion due to thrombus formation is a common challenge, especially for small-bore grafts with diameters less than 6 mm. There are generally two approaches to reduce coagulation in vascular grafts: (1) promote endothelial migration and seeding or (2) antithrombotic surface coatings. In the latter category, heparin-bonded grafts better maintain patency after 1 year but not after 5 years. (72) Thus, this presents an opportunity for developing novel polymer coatings to further improve long-term vascular graft performance.
Zwitterionic polymer coatings, particularly MPC, have been investigated to reduce protein fouling and increase vascular graft longevity. Yoneyama et al. evaluated a random copolymerized blend between polyurethane and MPC as a coating for 2–3 mm diameter Dacron graft. In a rabbit carotid artery end-to-end anastomosis model, they demonstrated that a 10% MPC blend maintained patency in three of the four rabbits for 8 weeks without anticoagulation. (48,49) A research team led by Dr. William Wagner and David Vorp synthesized their own biodegradable, poly(ester urethane) urea graft with electrospinning, treated the luminal surface with ammonia plasma to functionalize it with amine groups, and then attached MPC polymers. (45,51) Coated and uncoated vascular grafts were assessed in a rat abdominal aorta interposition graft placement model with a daily antiplatelet regimen. At the 8-week mark, the coated group maintained patency in 11 out of 12 rats, versus only 6 out of 15 in the uncoated group. One of the MPC-coated grafts maintained patency for 24 weeks.
Carboxybetaine and sulfobetaine polymers have also been studied for vascular graft applications, though not as extensively as phosphorylcholine. Drs. Sang-Ho Ye and William Wagner also developed a biodegradable, polyester sulfobetaine urethane urea graft material. (47) During in vitro, whole blood, incubation studies, the SB coating reduced platelet binding by 95% following 2 h of blood contact. Wang et al. synthesized biodegradable vascular grafts made of a keratin-based hydrogen disulfide donor, polycaprolactone, and a surface coating of PCB using polydopamine. (46) This graft was ultimately tested in a 1-month rat abdominal aorta implantation model. Their graft maintained its patency throughout the period, while displaying signs of vascular remodeling and controlled degradation of the original graft. Unfortunately, the group only reported data from only a single animal. Thus, while these results are positive, more long-term in vivo data are needed to evaluate the effectiveness of PSB and PCB for vascular grafts.

Artificial Lungs

Artificial lungs, commonly called “oxygenators”, contain dense bundles of layered, hollow fiber membranes with large, 1.3–1.8 m2, surface areas for adult applications. These semipermeable membranes are typically composed of polypropylene (PP) or polymethylpentene (PMP) with occasional devices with thin (≈1–2 μm) PDMS surface coatings. In addition to these surfaces, artificial lungs typically feature polycarbonate housings and polyurethane (PU) potting used to separate gas manifolds from blood passages. Blood flows externally to the hollow fibers at flow rates of 3–7 L/min and blood flow velocities of 50–135 cm/min for periods of several days to weeks. Due to the densely packed, high surface area fiber bundle, long periods of blood exposure, and relatively low blood flow velocity, artificial lungs are among the most procoagulant and prone to failure of all commercial blood-bearing medical devices. The median time of first artificial lung failure in most clinical studies is 8–9 days, with many devices developing occlusive clot formation that causes device dysfunction or failure within a few weeks. (73−81) Furthermore, the densely packed fiber bundles have overlapping hollow fibers and weaving fibers that result in numerous small areas that are challenging to coat effectively and feature static blood flow and poor washout of activated procoagulants. As a result, artificial lungs are the most challenging testbed for zwitterionic surface coatings.
Phosphorylcholine is the only zwitterionic polymer that is commercially available as an oxygenator coating. Phosphorylcholine coatings are marketed as Phisio coatings in LivaNova INSPIRE and Eurosets AMG oxygenators. Clinical reports on these oxygenators are heavily focused on patient outcomes and systemic inflammation following cardiopulmonary bypass surgeries. In these procedures, oxygenators are used for less than 6 h with a high degree of systemic anticoagulation, often without an uncoated control. (82−84) As such, the coating’s ability to resist clot formation is not commonly documented. Clinical reports of phosphorylcholine coating performance during longer-duration ECMO also do not report on their antithrombotic performance. (85) Thus, there is no evidence which proves that the commercial, Phisio, phosphorylcholine coating provides substantial surface-based anticoagulation in the challenging, long-term ECMO setting.
This lack of evidence has motivated the development of new zwitterionic surface coatings that can resist thrombus formation on artificial lungs. The first such coating was developed through collaboration from the laboratories of Dr. Shaoyi Jiang and the authors of this review article. That collaboration focused on exploring a facile coating approach for surface modification of the artificial lung. (41,43) A method was desired to provide a wash-through coating method that does not disrupt the normal artificial lung manufacturing process and is capable of coating the different hydrophobic polymer surfaces within an oxygenator, including PP, PMP, polycarbonate, and PU. Thus, Sundaram et al. first developed a flow-through, graft-from approach using DOPA to anchor pCBMA to the surfaces. (43) Following successful studies on flat sheets (41) (see also Performance of Zwitterionic Coatings on Flat Surfaces), these coatings were then tested on full devices. Ukita et al. then evaluated three types of grafting approaches in miniaturized artificial lungs (mini-lungs): graft-to using either (a) four DOPA or (b) random block copolymerization with hydrophobic moieties and (c) graft-from approach using atom transfer radical polymerase (ATRP). (44) Each coating was applied in mini-lungs with PDMS-coated polypropylene hollow fiber membranes. These three types of coated devices were then placed in parallel with an uncoated control and simultaneously tested in a sheep model of veno–venous ECMO using no systemic anticoagulation for 36 h. In this highly procoagulant setting, uncoated controls began to clot and fail after 7 h, with 60% failed by hour 36. In contrast, the DOPA-pCBMA coated devices began to fail at hour 35, and only 20% had failed by hour 36 (Figure 5). There was little to no benefit in the ATRP and block copolymer groups. A follow-up rabbit ECMO experiment then evaluated the circuit coated tip-to-tip with the DOPA-pCBMA approach, and the coating reduced clot formation by 59% compared to the uncoated control. (44) The team’s subsequent investigation reported on combining the DOPA-pCBMA coating with a bicyclic peptide Factor XIIa (FXIIa) inhibitor during short-term (1 h) rabbit ECMO. (7) The pCBMA coating alone reduced clot formation by 75% vs uncoated controls using heparin anticoagulation, while the combination of pCBMA coating with FXIIa inhibition reduced clot formation by 94%. Furthermore, the combination of pCBMA coating plus FXIIa inhibition preserved normal tissue coagulation. Lastly, Amoako et al. recently examined coating artificial lungs with commercially available pSBMA. (86) Resistance to protein adsorption by this coating was less effective than other, similar studies (45% of the control), but the coating was similarly effective at reducing platelet adhesion (16% of the control) following 90 min of incubation with platelet-rich plasma.

Figure 5

Figure 5. Artificial lung coating via pCBMA using a 4-DOPA attachment method (A) and resulting in vivo, artificial lung blood flow resistance vs time (B) demonstrating reduced clot formation leading to lower blood flow resistance over 36 h. Adapted with permission from ref (44). Copyright 2019 ACTA Biomaterialia.

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Dr. William Wagner, Sang Ho Ye, and William Federspiel have developed zwitterionic sulfobetaine block copolymer coatings for artificial lung applications. (87,88) Initially, their effort focused solely on the hollow fiber membranes, and used fibers that were initially aminated or hydroxylated to enable a graft-from polymerization approach. These coatings demonstrated an 80–95% reduction in platelet deposition after 3 h of whole blood exposure. Over time, this team has transitioned to establishing a more universal coating approach that can provide surface coverage across multiple types of hydrophobic polymers that exist within an ECMO circuit. (87) In their most recent work, they presented their pSB coating copolymerized with epoxy and siloxane, which showed versatility in the types of surfaces that can be coated, aqueous solubility, and the minimal need for plasma oxygen surface pretreatment. (89) The team also demonstrated that when the coating was incorporated onto a full-scale artificial lung made with a PMP fiber bundle, oxygen and carbon dioxide transfer rates were not significantly affected by the presence of coating, and platelet deposition was reduced by approximately 85% after 2 h of whole blood contact.
The lab of Yong-Kuan Gong has developed a cross-linkable, phosphorylcholine coating for artificial lungs. Their original coating was developed from a copolymerization scheme between zwitterionic phosphorylcholine, hydrophobic butyl methacrylate, and cross-linkable trimethoxysilyl side chains, such that the coating is grafted using hydrophobic interactions and further anchored to surfaces by cross-linking. (90,91) Their polymer coating has been applied on bare polypropylene hollow fiber membrane and tested for 2 h in their canine model of ECMO. In this animal study, the coating showed significantly better preservation of fibrinogen and platelet counts in blood and reduced platelet activation and thrombus burden on fiber surfaces when compared to the uncoated controls. (90) In more recent studies, this group has been incorporating heparin molecules into their phosphorylcholine coating for added anticoagulation effect, and using it to coat not only artificial lung membrane surfaces but also pumps, tubing, and connectors. They have also used parallel ECMO circuits, similar to Ukita et al., (44) in a pig model to confirm the efficacy of the coating in a clinical oxygenator for a period of 16 h. (92) At the same time, this group has primarily used bare microporous polypropylene for the artificial lung fiber bundle in their studies, which is contraindicated for extended ECMO use due to the risk of plasma leakage through its micropores. (93)
In sum, zwitterionic coatings on artificial lungs have demonstrated their ability to reduce protein adsorption, platelet binding, and clot formation over periods of up to 36 h. This is despite these devices being the most challenging testbed of all blood bearing medical devices. However, further work is needed to examine their function vs uncoated controls over more typical ECMO periods of one to 3 weeks.

Artificial Kidneys

Dialyzers (artificial kidneys), like artificial lungs, contain bundles of hollow fiber membranes with surface areas on the order of 1–2 m2. These semipermeable membranes are typically composed of polysulfone (PS), poly(ether sulfone) (PES), polyester polymer alloy (PEPA), polyacrylonitrile (PAN), and poly(methyl methacrylate) (PMMA). (94) However, the blood flow rates, blood flow patterns, and durations of blood contact are considerably different between dialyzers and artificial lungs. Dialyzers typically experience blood flows of less than 0.5 L/min and velocities of 60–180 cm/min (95) for periods ranging from only a few hours in patients with chronic renal insufficiency to several days in patients with acute renal failure.
Additionally, blood flow within dialyzers follows a straight path parallel to the hollow fiber bundle. Anticoagulation of dialyzers is less challenging than artificial lungs due to their shorter duration of use and the flexibility to change out failed devices without significant patient complications. That said, activation of inflammation is a much greater concern during hemodialysis than during artificial lungs. (96) The initiation of ECMO, and the initial exposure of blood to the artificial materials in the ECMO circuit leads to activation of complement and the contact system, generating numerous pro-inflammatory mediators. However, this fades after the first few days, making it a small issue over a period of support lasting a few weeks. Chronic kidney disease patients, in contrast, undergo intermittent hemodialysis three times per week for periods of only a few hours. This leads to repeated exposure of blood to artificial materials that are not yet fouled by plasma proteins and repeated activation of pro-inflammatory mediators, primarily complement. (22,24,97−99) This, in turn, leads to endothelial dysfunction, atherosclerosis, and chronic cardiovascular disease. (97)
Published research in this space focuses on optimization of zwitterionic polymer grafting on surfaces like cellulose and polysulfone, and quantification of antifouling performance in simple media. (100−104) These studies demonstrate reduced protein adsorption and platelet and bacterial adhesion with sustained filtration function. (100,102,104) However, more studies are needed to evaluate contact system and complement activation in a more clinically relevant setting, including multiple hours of whole blood contact.

Microfluidic Lungs and Kidneys

Microfluidic technology is gaining attention for achieving small-scale, compact organ support devices. Theoretically, these devices can achieve mass transfer profiles that are more efficient in space than the conventional artificial organ technology by minimizing the diffusion lengths. But due to the narrow cross-sectional area, the blood channels are prone to rapid occlusive thrombosis and premature failure. Surface coatings including PEG (105−108) and heparin (109) have been used most commonly to reduce thrombosis, while zwitterionic polymers have only been investigated by a few research teams. Dr. Joseph Potkay’s group evaluated sulfobetaine silane modification for their PDMS-based microfluidic lungs, demonstrating a 96% reduction in platelet adhesion under in vitro flow. (107) Dr. William Wagner’s group also reported on their self-segregating zwitterionic group-bearing PDMS technique, formulated by mixing diallyl-terminated sulfobetaine (SB-diallyl) within a commercial PDMS base. (57) This PDMS-SB formulation was used to fabricate microfluidic channel devices, and their blood-biocompatibility was tested by flowing blood with a low level of anticoagulation (0.625 units of heparin/mL blood). The PDMS-SB microfluidic channel was able to maintain patency for 1 h without any signs of occlusion, while the PDMS control device rapidly occluded from thrombosis. This microfabrication approach is promising as it does not require additional surface modification processes, and it may also potentially provide a more uniform surface coverage of zwitterions than a graft-to method. However, further work, particularly long-term in vivo testing, is still needed. Nevertheless, recent investigations by Borenstein’s group and their collaborators showed 24-h maintenance of their microfluidic lung device at a blood flow rate of 750 mL/min in a pig extracorporeal circulation model without any surface modifications. (110,111) While these results are encouraging, animals in these studies were given supratherapeutic heparin anticoagulation (i.e., activated clotting time above 250 s). Surface modifications of microfluidic devices will likely help reduce this heavy anticoagulation requirement. A multimodal strategy that combines zwitterionic surface coating and surface-focused anticoagulation using NO or contact system inhibitors, as discussed previously, could be promising for these devices. (7,41,54)
More recently, zwitterionic coatings have also been applied to microfluidic artificial kidneys being developed for permanent support of patients with chronic renal disease. Dr. Shuvo Roy has been developing a biohybrid artificial kidney with nanoporous silicon membranes. Dr. Roy’s group first applied PSB coatings to these membranes, demonstrating a greater than 80% reduction in albumin and fibrinogen adsorption from single protein solutions and 10% plasma (112,113) and almost complete elimination of platelet adhesion following 2 h of whole blood exposure. (112) Their group then went on to investigate the impact of different means of sterilization on zwitterionic coatings applied to silicon. Overall, they found that these coatings can largely maintain their coating thickness and hydrophilicity following a wide variety of sterilization methods, but that e-beam is best suited for PSB and ethylene oxide was best for PMPC. (114) Lastly, they evaluated platelet adhesion and activation and coagulation on PSB-coated silicon for 26-days in two pigs. (112) These studies demonstrated no clot formation using the coating, and no increase in platelet adhesion from 6 h to 26 days. However, there was increasing platelet activation over the study. Unfortunately, these studies contained no uncoated control, likely due to the great cost of these studies, leaving it unclear if the coating itself was the cause of the excellent long-term resistance to clot formation. Lastly, the team of Dr. Buddy Ratner and Dr. Jonathan Himmelfarb have applied zwitterionic surface coatings to their wearable artificial kidney, although no data on its effectiveness have yet been published. (115)

Ventricular Assist Devices (VADs)

Unlike the other devices discussed here, artificial hearts have a relatively small surface area with a relatively high blood flow velocity. As a result, thrombosis in artificial hearts is predominantly induced by high shear, leading to platelet and von Willebrand factor activation, increased levels of fluid recirculation and stasis, and buildup of activated procoagulants and platelets. Pump thrombosis has historically been a common clinical problem, occurring as frequently as 8–15% of patients who were implanted with the HeartMate II from Abbott and Thoratec. (116,117) Thus, the primary means of reducing thrombosis comes from careful design of device velocity and shear patterns, which was reflected in the next generation HeartMate 3 that reported thrombosis incident of only 1.1%. (118) Nevertheless, zwitterionic surface coatings still have the potential to further reduce thrombotic complications. Of note, the lab of Dr. Wagner has worked on zwitterionic coatings on titanium surfaces and applied them to VADs. Initially, MPC was applied to the EVAHEART VAD and evaluated preclinically over periods of one to six months. (119,120) When compared to diamond-like carbon coatings, the MPC coatings showed similar levels of biocompatibility, with potentially a small benefit to preserving platelets multiple weeks after implantation. Since that time, Dr. Wagner and Dr. Ye have covalently attached both PC and SB zwitterions to the titanium alloy, TiAl6V4, demonstrating large reductions in platelet adhesion after 2 h of whole blood exposure. (121)

Conclusions, Current Challenges, and Future Studies

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Zwitterionic MPC, PSB, and PCB coatings have been developed and tested for various blood-bearing medical device applications. This includes surface coatings of a wide variety of biomedical materials in medical-grade tubing, vascular grafts, and artificial lungs, kidneys, and hearts. Overall, the results clearly demonstrate the ability of these coatings to create large reductions in protein adsorption and platelet adhesion for several hours to a few days. The results are particularly promising for medical devices in which the predominant cause of clotting is the artificial surfaces themselves, as in artificial lungs and kidneys, rather than shear-induced platelet activation, as in ventricular assist devices. This suggests that these surfaces could play a major future role in the success of artificial lungs and kidneys intended for permanent support. (78,79,87−91)
Despite the success of these coatings, work is required to provide translational benefits in these emerging, challenging, long-term applications. While MPC coatings are now used clinically for periods of days to weeks, there is still no clear data on the performance of any of these coatings over that time frame when compared to uncoated controls. The stability of these coatings under whole blood contact has been particularly understudied and may require further coating optimization for these settings. Additionally, each medical device has its own unique geometry, blood flow velocities and shear stresses, potential mass transport through the coated surface (e.g., artificial lungs and kidneys), duration of use and manufacturing methods. Each device, therefore, may demand a slightly different coating technique, including the means of surface attachment and the coating thickness.
The relationship between device blood flow conditions and coating technique, stability, and effectiveness is also not known. This needs to be better studied so that the ideal coating approach can be applied for the specific device application. Multiple means of coating failure are possible, including mechanical and chemical degradation. Shear can cause erosion of thin coatings, (31) and chemical degradation is also possible, particularly during in vivo use with an active immune system capable of molecular degradation. As a result, additional means of stabilizing surface coatings may be necessary for applications lasting multiple days to weeks, including cross-linking, thicker coating layers, modified long-chain backbone chemistry, and coatings with the potential for self-renewal such as self-segregating PDMS. Lastly, surface coatings that are uneven can result in multiple point failures where small regions of protein adsorption grow to larger regions of occlusive clot via platelet adhesion and clot propagation. In this case, long-term use of a device, particularly with a low level of systemic anticoagulation, can lead to occlusive clot formation even if most of the device’s surfaces remain antiadsorptive. Thus, additional work may be required to develop coating methods that coat all regions of complex medical devices equally, particularly in devices with complex geometries and flow patterns such as artificial organs.
The method of evaluating coating biocompatibility also requires standardization. The wide variation in the selection of test medium (single protein solution, plasma, or whole blood), flow condition (static incubation or flow), and duration of testing further complicates the interpretation of data between published studies. Due to cost, initial studies are likely to continue to use single protein solutions and plasma on small material samples. However, even within this, the proteins and periods of testing require greater consistency. Thereafter, in vivo experiments featuring whole blood exposure will likely continue to be the gold standard. These experiments are highly expensive but continue to provide the most realistic picture of coating performance by evaluating the coatings under similar biochemical and fluid mechanical settings as their clinical applications. Thus, these studies will continue to vary, based largely on the medical device being tested.
Lastly, future studies should also consider more evaluations of the relative benefits of MPC, PSB, and PCB. Each can be used to coat materials in similar fashions, but there is little information on which zwitterion provides the most benefit with the same coating methods and test setting. The amount of published data is unfortunately scant. Additional data almost certainly exists, as various groups have experimented with different zwitterions for coating the same medical device. However, due to the cost of research and our publication culture, researchers all tend to play the winner, and thus lose important information on what approaches may be good but perhaps less than ideal.
With or without this work, zwitterionic surface coatings are likely to play a growing role in the use of blood-bearing medical devices due to their effectiveness at limiting protein adsorption, platelet adhesion, and surface clot formation. This will be particularly true in the case of current medical therapies that will be applied for longer use periods, including artificial lungs, artificial kidneys, and techniques applying both, such as long-term, ex-vivo organ perfusion.

Author Information

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  • Corresponding Author
  • Authors
    • Kagya Amoako - Department of Chemistry and Chemical and Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States;  Orcidhttps://orcid.org/0000-0002-2150-5214
    • Rei Ukita - Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37240, United States
  • Author Contributions

    K.A. and R.U. contributed equally.

  • Notes
    The authors declare no competing financial interest.

References

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    Chen, Xiaoyun; Wang, Jie; Paszti, Zoltan; Wang, Fulin; Schrauben, Joel N.; Tarabara, Volodymyr V.; Schmaier, Alvin H.; Chen, Zhan
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    Electrostatic interactions between neg. charged polymer surfaces and factor XII (FXII), a blood coagulation factor, were investigated by sum frequency generation (SFG) vibrational spectroscopy, supplemented by several anal. techniques including attenuated total reflection Fourier transform IR spectroscopy (ATR-FTIR), quartz crystal microbalance (QCM), ζ-potential measurement, and chromogenic assay. A series of sulfonated polystyrenes (sPS) with different sulfonation levels were synthesized as model surfaces with different surface charge densities. SFG spectra collected from FXII adsorbed onto PS and sPS surfaces with different surface charge densities showed remarkable differences in spectral features and esp. in spectral intensity. Chromogenic assay expts. showed that highly charged sPS surfaces induced FXII autoactivation. ATR-FTIR and QCM results indicated that adsorption amts. on the PS and sPS surfaces were similar even though the surface charge densities were different. No significant conformational change was obsd. from FXII adsorbed onto surfaces studied. Using theor. calcns., the possible contribution from the third-order nonlinear optical effect induced by the surface elec. field was evaluated, and it was found to be unable to yield the SFG signal enhancement obsd. Therefore it was concluded that the adsorbed FXII orientation and ordering were the main reasons for the remarkable SFG amide I signal increase on sPS surfaces. These investigations indicate that neg. charged surfaces facilitate or induce FXII autoactivation on the mol. level by imposing specific orientation and ordering on the adsorbed protein mols.
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    Biocompatibility of Hemodialysis Membranes: Interrelations between Plasma Complement and Cytokine Levels
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    Blood Purification (2001), 19 (4), 370-379CODEN: BLPUDO; ISSN:0253-5068. (S. Karger AG)
    Hemodialysis (HD) membrane biocompatibility is defined as absence of complement activation. We have recently shown that circulating levels of interleukin (IL) 1 and IL-2 predict death and survival, resp., of HD patients. Studies have assessed IL-1 in treatments with biocompatible and less biocompatible dialysis membranes, but no study has correlated circulating levels of all these immunoreactants. We assessed these immunoreactants, and temp. as an outcome, during HD in patients treated with different membranes. Twelve stable patients, receiving thrice-weekly chronic bicarbonate HD, were randomly dialyzed with three different types of membranes, composed of: Cuprophan, cuprammonium rayon modified cellulose, and Hemophan. Blood was drawn from the arterial line port before (Pre) and 15, 30, and 60 min during and after (Post) HD. Patients' temps. were measured before and after each treatment. The plasma concns. of IL-1 and IL-2 and factors C3a and C5a were assessed by ELISA. There were no differences between baseline levels of any of the immunoreactants in patients treated with different dialyzers. C3a, C5a, and IL-1 levels increased significantly during HD treatments with all three different membranes. C3a, C5a, and IL-1 levels during Cuprophan and Hemophan treatments were significantly higher than the levels during modified cellulose treatment at 30 and 60 min and Post (p < 0.01). For all the immunoreactants, however, the Post levels were higher than the Pre levels. In contrast to IL-1, there were no differences in mean IL-2 levels during treatments when different membranes were compared. There were few correlations of plasma C3a and C5a levels with plasma IL-1 levels, but there was only one treatment time in one dialyzer group during which IL-2 and any of the other factors were correlated. Pre and Post temp. values and percent change in temp. were not correlated with any of the immunoreactants measured. These data show that C3a, C5a, and IL-1 responses are similar, but not identical, during treatments with different membranes. The response of circulating IL-2 levels to treatments is quite different from that of plasma C3a, C5a and IL-1 levels and suggests that these changes are not solely due to treatment factors. Treatment with modified cellulose membranes is assocd. with a different immunoreactive profile as compared with patients dialyzed using other cellulose membranes. We suggest that circulating IL-1 levels are good biocompatibility markers.
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    Ibrahim, M.; Ramadan, E.; Elsadek, N. E. Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products. J. Controlled Release 2022, 351, 215– 230,  DOI: 10.1016/j.jconrel.2022.09.031
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    Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products
    Ibrahim, Mohamed; Ramadan, Eslam; Elsadek, Nehal E.; Emam, Sherif E.; Shimizu, Taro; Ando, Hidenori; Ishima, Yu; Elgarhy, Omar Helmy; Sarhan, Hatem A.; Hussein, Amal K.; Ishida, Tatsuhiro
    Journal of Controlled Release (2022), 351 (), 215-230CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    A review. Polyethylene glycol (PEG) is a versatile polymer that is widely used as an additive in foods and cosmetics, and as a carrier in PEGylated therapeutics. Even though PEG is thought to be less immunogenic, or perhaps even non-immunogenic, with a variety of physicochem. properties, there is mounting evidence that PEG causes immunogenic responses when conjugated with other materials such as proteins and nanocarriers. Under these conditions, PEG with other materials can result in the prodn. of anti-PEG antibodies after administration. The antibodies that are induced seem to have a deleterious impact on the therapeutic efficacy of subsequently administered PEGylated formulations. In addn., hypersensitivity to PEGylated formulations could be a significant barrier to the utility of PEGylated products. Several reports have linked the presence of anti-PEG antibodies to incidences of complement activation-related pseudoallergy (CARPA) following the administration of PEGylated formulations. The use of COVID-19 mRNA vaccines, which are composed mainly of PEGylated lipid nanoparticles (LNPs), has recently gained wide acceptance, although many cases of post-vaccination hypersensitivity have been documented. Therefore, our review focuses not only on the importance of PEGs and its great role in improving the therapeutic efficacy of various medications, but also on the hypersensitivity reactions attributed to the use of PEGylated products that include PEG-based mRNA COVID-19 vaccines.
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    Molecular understanding and design of zwitterionic materials
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    Advanced Materials (Weinheim, Germany) (2015), 27 (1), 15-26CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Zwitterionic materials have moieties possessing cationic and anionic groups. This mol. structure leads to unique properties that can be the solns. of various application problems. A typical example is that zwitterionic carboxybetaine (CB) and sulfobetaine (SB) materials resist nonspecific protein adsorption in complex media. Considering the vast no. of cationic and anionic groups in the current chem. inventory, there are many possible structural variations of zwitterionic materials. The diversified structures provide the possibility to achieve many desired properties and urge a better understanding of zwitterionic materials to provide design principles. Mol. simulations and modeling are a versatile tool to understand the structure-property relationships of materials at the mol. level. This progress report summarizes recent simulation and modeling studies addressing two fundamental questions regarding zwitterionic materials and their applications as biomaterials. First, what are the differences between zwitterionic and nonionic materials. Second, what are the differences among zwitterionic materials. This report also demonstrates a mol. design of new protein-resistant zwitterionic moieties beyond conventional CB and SB based on design principles developed from these simulation studies.
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    Ultrathin Antifouling Coatings with Stable Surface Zwitterionic Functionality by Initiated Chemical Vapor Deposition (iCVD)
    Yang, Rong; Gleason, Karen K.
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    Antifouling thin films of poly[N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)-co-2-(dimethylamino)ethyl methacrylate-co-ethylene glycol dimethacrylate] (PDDE) were synthesized via a substrate-independent and all-dry-initiated chem. vapor deposition (iCVD) technique followed by a diffusion-limited vapor-phase reaction with 1,3-propane sultone. Coated surfaces exhibited very low absorption of various foulants including bovine serum albumin (BSA), humic acid (HA), and sodium alginate (SA), as measured with the quartz crystal microbalance with dissipation monitoring (QCM-D). The fouling by humic acid was dependent on the presence of divalent cations such as Ca2+. Both depth profiling and angle-resolved XPS measurements indicated that the zwitterionic groups were highly concd. in the top ∼3 nm of the film. The contact angle measurements revealed a limited degree of surface chain reorganization upon contacting water. The dynamic contact angles remained unchanged after 100 days of storage in air, indicating the stability of the interface. The coating was substrate-independent, and the film was conformal on surface nanostructures including trenches, reverse osmosis membranes, and electrospun nanofiber mats.
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    Designing polymer surfaces via vapor deposition
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    Materials Today (Oxford, United Kingdom) (2010), 13 (5), 26-33CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)
    A review. Chem. Vapor Deposition [CVD] methods significantly augment the capabilities of traditional surface modification techniques for designing polymeric surfaces. In CVD polymn., the monomer(s) are delivered to the surface through the vapor phase and then undergo simultaneous polymn. and thin film formation. By eliminating the need to dissolve macromols., CVD enables insol. polymers to be coated and prevents solvent damage to the substrate. Since de-wetting and surface tension effects are absent, CVD coatings conform to the geometry of the underlying substrate. Hence, CVD polymers can be readily applied to virtually any substrate: org., inorg., rigid, flexible, planar, three-dimensional, dense, or porous. CVD methods integrate readily with other vacuum processes used to fabricate patterned surfaces and devices. CVD film growth proceeds from the substrate up, allowing for interfacial engineering, real-time monitoring, thickness control, and the synthesis of films with graded compn. This article focuses on two CVD polymn. methods that closely translate soln. chem. to vapor deposition; initiated CVD and oxidative CVD. The basic concepts underlying these methods and the resultant advantages over other thin film coating techniques are described, along with selected applications where CVD polymers are an enabling technol.
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    Chemical Reviews (Washington, DC, United States) (2005), 105 (4), 1103-1169CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
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    A review on the organization of complex, semiflexible org. mols. within quasi-2-D assemblies due to the delicate interplay between substrate-adsorbate interactions, nonbonded interactions between adsorbates, electrostatic and VDW forces, and intramol. interactions (e.g., bond stretches, angle bends, and torsions). Surface reorganization contributes to the final equil. structure of the assembly. Structural factors controlling the formation of self-assembled monolayers (SAMs) are discussed. Different SAMs with unique properties and potential applications are considered. An attempt is made to provide a general picture of self-assembly on solid surfaces as it emerges from a consideration of the interplay of different forces that control this process. 273 Refs.
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    Hong, D.; Hung, H. C.; Wu, K. Achieving Ultralow Fouling under Ambient Conditions via Surface-Initiated ARGET ATRP of Carboxybetaine. ACS Appl. Mater. Interfaces. 2017, 9 (11), 9255– 9259,  DOI: 10.1021/acsami.7b01530
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    Achieving Ultralow Fouling under Ambient Conditions via Surface-Initiated ARGET ATRP of Carboxybetaine
    Hong, Daewha; Hung, Hsiang-Chieh; Wu, Kan; Lin, Xiaojie; Sun, Fang; Zhang, Peng; Liu, Sijun; Cook, Keith E.; Jiang, Shaoyi
    ACS Applied Materials & Interfaces (2017), 9 (11), 9255-9259CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    We achieved ultralow fouling on target surfaces by controlled polymn. of carboxybetaine under ambient conditions. The polymn. process for grafting polymer films onto the surfaces was carried out in air and did not require any deoxygenation step or specialized equipment. This method allows one to conveniently introduce a nonfouling polymer network onto large substrates.
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    Sundaram, H. S.; Han, X.; Nowinski, A. K. Achieving One-step Surface Coating of Highly Hydrophilic Poly(Carboxybetaine Methacrylate) Polymers on Hydrophobic and Hydrophilic Surfaces. Adv. Mater. Interfaces. 2014, 1 (6), 1400071,  DOI: 10.1002/admi.201400071
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    Ukita, R.; Wu, K.; Lin, X. Zwitterionic poly-carboxybetaine coating reduces artificial lung thrombosis in sheep and rabbits. Acta Biomater. 2019, 92, 71– 81,  DOI: 10.1016/j.actbio.2019.05.019
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    Zwitterionic poly-carboxybetaine coating reduces artificial lung thrombosis in sheep and rabbits
    Ukita, Rei; Wu, Kan; Lin, Xiaojie; Carleton, Neil M.; Naito, Noritsugu; Lai, Angela; Do-Nguyen, Chi Chi; Demarest, Caitlin T.; Jiang, Shaoyi; Cook, Keith E.
    Acta Biomaterialia (2019), 92 (), 71-81CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Current artificial lungs fail in 1-4 wk due to surface-induced thrombosis. Biomaterial coatings may be applied to anticoagulate artificial surfaces, but none have shown marked long-term effectiveness. Poly-carboxybetaine (pCB) coatings have shown promising results in reducing protein and platelet-fouling in vitro. However, in vivo hemocompatibility remains to be investigated. Thus, three different pCB-grafting approaches to artificial lung surfaces were first investigated: 1) graft-to approach using 3,4-dihydroxyphenylalanine (DOPA) conjugated with pCB (DOPA-pCB); 2) graft-from approach using the Activators ReGenerated by Electron Transfer method of atom transfer radical polymn. (ARGET-ATRP); and 3) graft-to approach using pCB randomly copolymd. with hydrophobic moieties. One device coated with each of these methods and one uncoated device were attached in parallel within a veno-venous sheep extracorporeal circuit with no continuous anticoagulation (N = 5 circuits). The DOPA-pCB approach showed the least increase in blood flow resistance and the lowest incidence of device failure over 36-h. Next, we further investigated the impact of tip-to-tip DOPA-pCB coating in a 4-h rabbit study with veno-venous micro-artificial lung circuit at a higher activated clotting time of 220-300 s (N ≥ 5). Here, DOPA-pCB reduced fibrin formation (p = 0.06) and gross thrombus formation by 59% (p < 0.05). Therefore, DOPA-pCB is a promising material for improving the anticoagulation of artificial lungs. Chronic lung diseases lead to 168,000 deaths each year in America, but only 2300 lung transplantations happen each year. Hollow fiber membrane oxygenators are clin. used as artificial lungs to provide respiratory support for patients, but their long-term viability is hindered by surface-induced clot formation that leads to premature device failure. Among different coatings investigated for blood-contacting applications, poly-carboxybetaine (pCB) coatings have shown remarkable redn. in protein adsorption in vitro. However, their efficacy in vivo remains unclear. This is the first work that investigates various pCB-coating methods on artificial lung surfaces and their biocompatibility in sheep and rabbit studies. This work highlights the promise of applying pCB coatings on artificial lungs to extend its durability and enable long-term respiratory support for lung disease patients.
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    Hong, Y.; Ye, S. H.; Nieponice, A.; Soletti, L.; Vorp, D. A.; Wagner, W. R. A small diameter, fibrous vascular conduit generated from a poly(ester urethane)urea and phospholipid polymer blend. Biomaterials. 2009, 30 (13), 2457– 67,  DOI: 10.1016/j.biomaterials.2009.01.013
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    A small diameter, fibrous vascular conduit generated from a poly(ester urethane)urea and phospholipid polymer blend
    Hong, Yi; Ye, Sang-Ho; Nieponice, Alejandro; Soletti, Lorenzo; Vorp, David A.; Wagner, William R.
    Biomaterials (2009), 30 (13), 2457-2467CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    The thrombotic and hyperplastic limitations assocd. with synthetic small diam. vascular grafts have generated sustained interest in finding a tissue engineering soln. for autologous vascular segment generation in situ. One approach is to place a biodegradable scaffold at the site that would provide acute mech. support while vascular tissue develops. To generate a scaffold that possessed both non-thrombogenic character and mech. properties appropriate for vascular tissue, a biodegradable poly(ester urethane)urea (PEUU) and non-thrombogenic bioinspired phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine-co-methacryloyloxyethyl butylurethane) (PMBU) were blended at PMBU wt. fractions of 0-15% and electrospun to create fibrous scaffolds. The composite scaffolds were flexible with breaking strains exceeding 300%, tensile strengths of 7-10 MPa and compliances of 2.9-4.4 × 10-4 mmHg-1. In vitro platelet deposition on the scaffold surfaces significantly decreased with increasing PMBU content. Rat smooth muscle cell proliferation was also inhibited on PEUU/PMBU blended scaffolds with greater inhibition at higher PMBU content. Fibrous vascular conduits (1.3 mm inner diam.) implanted in the rat abdominal aorta for 8 wk showed greater patency for grafts with 15% PMBU blending vs. PEUU without PMBU (67% vs. 40%). A thin neo-intimal layer with endothelial coverage and good anastomotic tissue integration was seen for the PEUU/PMBU vascular grafts. These results are encouraging for further evaluation of this technique in larger diam. applications for longer implant periods.
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    Wang, L.; Miao, C.; Liang, F. Hydrogen sulfide releasing and carboxybetaine modified vascular graft with enhanced anticoagulant, anticalcification, and pro-endothelialization properties. Applied Materials Today. 2023, 35, 101976,  DOI: 10.1016/j.apmt.2023.101976
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    Nonthrombogenic, Biodegradable Elastomeric Polyurethanes with Variable Sulfobetaine Content
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    ACS Applied Materials & Interfaces (2014), 6 (24), 22796-22806CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    For applications where degradable polymers are likely to have extended blood contact, it is often important for these materials to exhibit high levels of thromboresistance. This can be achieved with surface modification approaches, but such modifications may be transient with degrdn. Alternatively, polymer design can be altered such that the bulk polymer is thromboresistant and this is maintained with degrdn. Toward this end a series of biodegradable, elastic polyurethanes (PESBUUs) contg. different zwitterionic sulfobetaine (SB) content were synthesized from a polycaprolactone-diol (PCL-diol):SB-diol mixt. (100:0, 75:25, 50:50, 25:75 and 0:100) reacted with diisocyanatobutane and chain extended with putrescine. The chem. structure, tensile mech. properties, thermal properties, hydrophilicity, biodegradability, fibrinogen adsorption and thrombogenicity of the resulting polymers was characterized. With increased SB content some weakening in tensile properties occurred in wet conditions and enzymic degrdn. also decreased. However, at higher zwitterionic molar ratios (50% and 75%) wet tensile strength exceeded 15 MPa and breaking strain was >500%. Markedly reduced thrombotic deposition was obsd. both before and after substantial degrdn. for both of these PESBUUs and they could be processed by electrospinning into a vascular conduit format with appropriate compliance properties. The mech. and degrdn. properties as well as the acute in vitro thrombogenicity assessment suggest that these tunable polyurethanes could provide options appropriate for use in blood contacting applications where a degradable, elastomeric component with enduring thromboresistance is desired.
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    In vivo performance of a phospholipid-coated bioerodable elastomeric graft for small-diameter vascular applications
    Soletti, Lorenzo; Nieponice, Alejandro; Hong, Yi; Ye, Sang-Ho; Stankus, John J.; Wagner, William R.; Vorp, David A.
    Journal of Biomedical Materials Research, Part A (2011), 96A (2), 436-448CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)
    There remains a great need for vascular substitutes for small-diam. applications. The use of an elastomeric biodegradable material, enabling acute antithrombogenicity and long-term in vivo remodeling, could be beneficial for this purpose. Conduits (1.3 mm internal diam.) were obtained by electrospinning biodegradable poly(ester urethane)urea (PEUU), and by luminally immobilizing a non-thrombogenic, 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymer. Platelet adhesion was characterized in vitro after contact with ovine blood. The conduits were implanted as aortic interposition grafts in the rat for 4, 8, 12, and 24 wk. Surface treatment resulted in a 10-fold decrease in platelet adhesion compared to untreated material. Patency at 8 wk was 92% for the coated grafts compared to 40% for the non-coated grafts. Histol. at 8 and 12 wk demonstrated formation of cellularized neotissue consisting of aligned collagen and elastin. The lumen of the grafts was confluent with cells qual. aligned in the direction of blood flow. Immunohistochem. suggested the presence of smooth muscle cells in the medial layer of the neotissue and endothelial cells lining the lumen. Mech., the grafts were less compliant than rat aortas prior to implantation (4.5 ± 2.0 × 10-4 mmHg-1 vs. 14.2 ± 1.1 × 10-4 mmHg-1, resp.), then after 4 wk in vivo they approximated native values, but subsequently became stiffer again at later time points. The novel coated grafts exhibited promising antithrombogenic and mech. properties for small-diam. arterial revascularization. Further evaluation in vivo will be required to demonstrate complete remodeling of the graft into a native-like artery. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011.
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    Hou, Z.; Wu, Y.; Xu, C. Precisely Structured Nitric-Oxide-Releasing Copolymer Brush Defeats Broad-Spectrum Catheter-Associated Biofilm Infections In Vivo. ACS Cent Sci. 2020, 6 (11), 2031– 2045,  DOI: 10.1021/acscentsci.0c00755
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    Precisely Structured Nitric-Oxide-Releasing Copolymer Brush Defeats Broad-Spectrum Catheter-Associated Biofilm Infections In Vivo
    Hou, Zheng; Wu, Yang; Xu, Chen; Reghu, Sheethal; Shang, Zifang; Chen, Jingjie; Pranantyo, Dicky; Marimuth, Kalisvar; De, Partha Pratim; Ng, Oon Tek; Pethe, Kevin; Kang, En-Tang; Li, Peng; Chan-Park, Mary B.
    ACS Central Science (2020), 6 (11), 2031-2045CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    Gram-neg. bacteria cannot be easily eradicated by antibiotics and are a major source of recalcitrant infections of indwelling medical devices. Among various device-assocd. infections, intravascular catheter infection is a leading cause of mortality. Prior approaches to surface modification, such as antibiotics impregnation, hydrophilization, unstructured NO-releasing, etc., have failed to achieve adequate infection-resistant coatings. We report a precision-structured diblock copolymer brush (H(N)-b-S) composed of a surface antifouling block of poly(sulfobetaine methacrylate) (S) and a subsurface bactericidal block (H(N)) of nitric-oxide-emitting functionalized poly(hydroxyethyl methacrylate) (H) covalently grafted from the inner and outer surfaces of a polyurethane catheter. The block copolymer architecture of the coating is important for achieving good broad-spectrum anti-biofilm activity with good biocompatibility and low fouling. The coating procedure is scalable to clin. useful catheter lengths. Only the block copolymer brush coating ((H(N)-b-S)) shows unprecedented, above 99.99%, in vitro biofilm inhibition of Gram-pos. and Gram-neg. bacteria, 100-fold better than previous coatings. It has negligible toxicity toward mammalian cells and excellent blood compatibility. In a murine s.c. infection model, it achieves >99.99% biofilm redn. of Gram-pos. and Gram-neg. bacteria compared with <90% for silver catheter, while in a porcine central venous catheter infection model, it achieves >99.99% redn. of MRSA with 5-day implantation. This precision coating is readily applicable for long-term biofilm-resistant and blood-compatible copolymer coatings covalently grafted from a wide range of medical devices. We report a precisely structured anti-infective polymer brush coating on a catheter that defeats biofilms of Gram-pos. and Gram-neg. bacteria with good hemo- and biocompatibility and is thrombus- and protein-resistant.
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    Li, K.; Peng, J.; Liu, Y. Surface Engineering of Central Venous Catheters via Combination of Antibacterial Endothelium-Mimicking Function and Fibrinolytic Activity for Combating Blood Stream Infection and Thrombosis. Adv. Healthc Mater. 2023, 12 (23), e2300120  DOI: 10.1002/adhm.202300120
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    Singha, P.; Goudie, M. J.; Liu, Q. Multipronged Approach to Combat Catheter-Associated Infections and Thrombosis by Combining Nitric Oxide and a Polyzwitterion: a 7 Day In Vivo Study in a Rabbit Model. ACS Appl. Mater. Interfaces. 2020, 12 (8), 9070– 9079,  DOI: 10.1021/acsami.9b22442
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    Multipronged approach to combat catheter-associated infections and thrombosis by combining nitric oxide and a polyzwitterion: a 7 day in vivo study in a rabbit model
    Singha, Priyadarshini; Goudie, Marcus J.; Liu, Qiaohong; Hopkins, Sean; Brown, Nettie; Schmiedt, Chad W.; Locklin, Jason; Handa, Hitesh
    ACS Applied Materials & Interfaces (2020), 12 (8), 9070-9079CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    The development of nonfouling and antimicrobial materials has shown great promise for reducing thrombosis and infection assocd. with medical devices with aims of improving device safety and decreasing the frequency of antibiotic administration. Here, the design of an antimicrobial, anti-inflammatory, and antithrombotic vascular catheter is assessed in vivo over 7 d in a rabbit model. Antimicrobial and antithrombotic activity is achieved through the integration of a nitric oxide donor, while the nonfouling surface is achieved using a covalently bound phosphorylcholine-based polyzwitterionic copolymer topcoat. The effect of sterilization on the nonfouling nature and nitric oxide release is presented. The catheters reduced viability of Staphylococcus aureus in long-term studies (7 d in a CDC bioreactor) and inflammation in the 7 d rabbit model. Overall, this approach provides a robust method for decreasing thrombosis, inflammation, and infections assocd. with vascular catheters.
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    Smith, R. S.; Zhang, Z.; Bouchard, M. Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. Sci. Transl Med. 2012, 4 (153), 153ra132,  DOI: 10.1126/scitranslmed.3004120
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    Gokaltun, A. A.; Mazzaferro, L.; Yarmush, M. L.; Usta, O. B.; Asatekin, A. Surface-segregating zwitterionic copolymers to control poly(dimethylsiloxane) surface chemistry. J. Mater. Chem. B 2023, 12 (1), 145– 157,  DOI: 10.1039/D3TB02164E
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    Mercader, A.; Ye, S. H.; Kim, S.; Orizondo, R. A.; Cho, S. K.; Wagner, W. R. PDMS-Zwitterionic Hybrid for Facile, Antifouling Microfluidic Device Fabrication. Langmuir. 2022, 38 (12), 3775– 3784,  DOI: 10.1021/acs.langmuir.1c03375
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    Yang, W.; Bai, T.; Carr, L. R. The effect of lightly crosslinked poly (carboxybetaine) hydrogel coating on the performance of sensors in whole blood. Biomaterials. 2012, 33 (32), 7945– 7951,  DOI: 10.1016/j.biomaterials.2012.07.035
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    Xie, X.; Doloff, J. C.; Yesilyurt, V. Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer. Nat. Biomed Eng. 2018, 2 (12), 894– 906,  DOI: 10.1038/s41551-018-0273-3
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    Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer
    Xie, Xi; Doloff, Joshua C.; Yesilyurt, Volkan; Sadraei, Atieh; McGarrigle, James J.; Omami, Mustafa; Veiseh, Omid; Farah, Shady; Isa, Douglas; Ghani, Sofia; Joshi, Ira; Vegas, Arturo; Li, Jie; Wang, Weiheng; Bader, Andrew; Tam, Hok Hei; Tao, Jun; Chen, Hui-jiuan; Yang, Boru; Williamson, Katrina Ann; Oberholzer, Jose; Langer, Robert; Anderson, Daniel G.
    Nature Biomedical Engineering (2018), 2 (12), 894-906CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)
    Continuous glucose monitors (CGMs), used by patients with diabetes mellitus, can autonomously track fluctuations in blood glucose over time. However, the signal produced by CGMs during the initial recording period following sensor implantation contains substantial noise, requiring frequent recalibration via finger-prick tests. Here, we show that coating the sensor with a zwitterionic polymer, found via a combinatorial chem. approach, significantly reduces signal noise and improves CGM performance. We evaluated the polymer-coated sensors in mice as well as in healthy and diabetic non-human primates, and show that the sensors accurately record glucose levels without the need for recalibration. We also show that the coated sensors significantly abrogated immune responses, as indicated by histol., fluorescent whole-body imaging of inflammation-assocd. protease activity and gene expression of inflammation markers. The polymer coating may allow CGMs to become standalone measuring devices.
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    Jiang, S.; Cao, Z. Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv. Mater. 2010, 22 (9), 920– 32,  DOI: 10.1002/adma.200901407
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    Ultralow-Fouling, Functionalizable, and Hydrolyzable Zwitterionic Materials and Their Derivatives for Biological Applications
    Jiang, Shaoyi; Cao, Zhiqiang
    Advanced Materials (Weinheim, Germany) (2010), 22 (9), 920-932CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. In recent years, zwitterionic materials such as poly(carboxybetaine) (pCB) and poly(sulfobetaine) (pSB) have been applied to a broad range of biomedical and engineering materials. Due to electrostatically induced hydration, surfaces coated with zwitterionic groups are highly resistant to nonspecific protein adsorption, bacterial adhesion, and biofilm formation. Among zwitterionic materials, pCB is unique due to its abundant functional groups for the convenient immobilization of biomols. pCB can also be prepd. in a hydrolyzable form as cationic pCB esters, which can kill bacteria or condense DNA. The hydrolysis of cationic pCB esters into nonfouling zwitterionic groups will lead to the release of killed microbes or the irreversible unpackaging of DNA. Furthermore, mixed-charge materials have been shown to be equiv. to zwitterionic materials in resisting nonspecific protein adsorption when they are uniformly mixed at the mol. scale.
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    Keefe, A. J.; Jiang, S. Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity. Nat. Chem. 2012, 4 (1), 59– 63,  DOI: 10.1038/nchem.1213
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    Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity
    Keefe, Andrew J.; Jiang, Shaoyi
    Nature Chemistry (2012), 4 (1), 59-63CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    Treatment with therapeutic proteins is an attractive approach to targeting a no. of challenging diseases. Unfortunately, the native proteins themselves are often unstable in physiol. conditions, reducing bioavailability and therefore increasing the dose that is required. Conjugation with poly(ethylene glycol) (PEG) is often used to increase stability, but this has a detrimental effect on bioactivity. Here, we introduce conjugation with zwitterionic polymers such as poly(carboxybetaine). We show that poly(carboxybetaine) conjugation improves stability in a manner similar to PEGylation, but that the new conjugates retain or even improve the binding affinity as a result of enhanced protein-substrate hydrophobic interactions. This chem. opens a new avenue for the development of protein therapeutics by avoiding the need to compromise between stability and affinity.
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    Ishihara, K. Highly lubricated polymer interfaces for advanced artificial hip joints through biomimetic design. Polymer Journal. 2015, 47 (9), 585– 597,  DOI: 10.1038/pj.2015.45
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    Cheng, G.; Xue, H.; Zhang, Z.; Chen, S.; Jiang, S. A Switchable Biocompatible Polymer Surface with Self-Sterilizing and Nonfouling Capabilities. Angewandte Chemie International Edition. 2008, 47 (46), 8831– 8834,  DOI: 10.1002/anie.200803570
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    Li, G.; Cheng, G.; Xue, H.; Chen, S.; Zhang, F.; Jiang, S. Ultra low fouling zwitterionic polymers with a biomimetic adhesive group. Biomaterials. 2008, 29 (35), 4592– 7,  DOI: 10.1016/j.biomaterials.2008.08.021
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    Ultra low fouling zwitterionic polymers with a biomimetic adhesive group
    Li, Guozhu; Cheng, Gang; Xue, Hong; Chen, Shengfu; Zhang, Fengbao; Jiang, Shaoyi
    Biomaterials (2008), 29 (35), 4592-4597CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Biomimetic polymers with a zwitterionic moiety for ultra low fouling and a catechol end group for surface anchoring have been developed. Binding tests of the adhesive polymers on various surfaces, including amino (NH2), hydroxyl (OH), and Me (CH3) terminated self-assembled monolayers (SAMs) along with bare gold, were performed under acidic and basic conditions. Protein adsorption from single protein solns. of fibrinogen, lysozyme, and complex media of 10-100% blood plasma and serum was measured using a surface plasmon resonance (SPR) sensor. Under optimized conditions, the coated surfaces are highly resistant to non-specific protein adsorption from both single protein solns. and blood serum/plasma. Furthermore, the 3-day accumulation of Pseudomonas aeruginosa on the coated surfaces was evaluated in situ in a laminar flow chamber. Results show that the coated surfaces are highly resistant to bacterial adhesion and biofilm formation. This work demonstrates a convenient and efficient method for using zwitterionic polymers with a catechol anchor group to achieve ultra low fouling surfaces via surface modification, for applications in complex media.
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    Zhang, L.; Cao, Z.; Bai, T. Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat. Biotechnol. 2013, 31 (6), 553– 6,  DOI: 10.1038/nbt.2580
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    Zwitterionic hydrogels implanted in mice resist the foreign-body reaction
    Zhang, Lei; Cao, Zhiqiang; Bai, Tao; Carr, Louisa; Ella-Menye, Jean-Rene; Irvin, Colleen; Ratner, Buddy D.; Jiang, Shaoyi
    Nature Biotechnology (2013), 31 (6), 553-556CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    The performance of implantable biomedical devices is impeded by the foreign-body reaction, which results in formation of a dense collagenous capsule that blocks mass transport and/or elec. communication between the implant and the body. No known materials or coatings can completely prevent capsule formation. Here we demonstrate that ultra-low-fouling zwitterionic hydrogels can resist the formation of a capsule for at least 3 mo after s.c. implantation in mice. Zwitterionic hydrogels also promote angiogenesis in surrounding tissue, perhaps owing to the presence of macrophages exhibiting phenotypes assocd. with anti-inflammatory, pro-healing functions. Thus, zwitterionic hydrogels may be useful in a broad range of applications, including generation of biocompatible implantable medical devices and tissue scaffolds.
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    Golabchi, A.; Wu, B.; Cao, B.; Bettinger, C. J.; Cui, X. T. Zwitterionic polymer/polydopamine coating reduce acute inflammatory tissue responses to neural implants. Biomaterials. 2019, 225, 119519,  DOI: 10.1016/j.biomaterials.2019.119519
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    Zwitterionic polymer/polydopamine coating reduce acute inflammatory tissue responses to neural implants
    Golabchi, Asiyeh; Wu, Bingchen; Cao, Bin; Bettinger, Christopher J.; Cui, Xinyan Tracy
    Biomaterials (2019), 225 (), 119519CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    The inflammatory brain tissue response to implanted neural electrode devices has hindered the longevity of these implants. Zwitterionic polymers have a potent anti-fouling effect that decreases the foreign body response to s.c. implants. In this study, we developed a nanoscale anti-fouling coating composed of zwitterionic poly (sulfobetaine methacrylate) (PSB) and polydopamine (PDA) for neural probes. The addn. of PDA improved the stability of the coating compared to PSB alone, without compromising the anti-fouling properties of the film. PDA-PSB coating reduced protein adsorption by 89% compared to bare Si samples, while fibroblast adhesion was reduced by 86%. PDA-PSB coated silicon based neural probes were implanted into mouse brain, and the inflammatory tissue responses to the implants were assessed by immunohistochem. one week after implantation. The PSB-PDA coated implants showed a significantly decreased expression of glial fibrillary acidic protein (GFAP), a marker for reactive astrocytes, within 70 μm from the electrode-tissue interface (p < 0.05). Addnl., the coating reduced the microglia activation as shown in decreased Iba-1 and lectin staining, and improved blood-brain barrier integrity indicated by reduced Ig (IgG) leakage into the tissue around the probes. These findings demonstrate that anti-fouling zwitterionic coating is effective in suppressing the acute inflammatory brain tissue response to implants, and should be further investigated for its potential to improve chronic performance of neural implants.
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    Thorarinsdottir, H.; Kander, T.; Johansson, D.; Nilsson, B.; Klarin, B.; Sanchez, J. Blood compatibility of widely used central venous catheters; an experimental study. Sci. Rep. 2022, 12 (1), 8600,  DOI: 10.1038/s41598-022-12564-z
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    Lai, N. M.; Chaiyakunapruk, N.; Lai, N. A.; O’Riordan, E.; Pau, W. S.; Saint, S. Catheter impregnation, coating or bonding for reducing central venous catheter-related infections in adults. Cochrane Database Syst. Rev. 2016, 3 (3), CD007878  DOI: 10.1002/14651858.CD007878.pub3
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    Verso, M.; Agnelli, G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J. Clin Oncol. 2003, 21 (19), 3665– 75,  DOI: 10.1200/JCO.2003.08.008
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    Citla Sridhar, D.; Abou-Ismail, M. Y.; Ahuja, S. P. Central venous catheter-related thrombosis in children and adults. Thromb Res. 2020, 187, 103– 112,  DOI: 10.1016/j.thromres.2020.01.017
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    Central venous catheter-related thrombosis in children and adults
    Citla Sridhar, Divyaswathi; Abou-Ismail, Mouhamed Yazan; Ahuja, Sanjay P.
    Thrombosis Research (2020), 187 (), 103-112CODEN: THBRAA; ISSN:0049-3848. (Elsevier Ltd.)
    Central venous catheters (CVC) have revolutionized the care of patients requiring long-term venous access. With increasing use of CVCs, the incidence of catheter-related thrombosis (CRT) has been on the rise. CRT constitutes 10% of all deep venous thromboses (DVT) in adults and 50-80% of all DVTs among children. The incidence of CRT varies significantly based on patient characteristics, catheter-related factors and the steps involved in the process of catheter insertion. Multiple risk factors have been assocd. with a higher risk of CRT, including older age, hospitalization, CVC insertion in the subclavian vein, left-sided CVC insertion, longer duration of catheter, catheter-to-vein ratio > 0.45, and type of CVC. A majority of patients with CRT are asymptomatic. Duplex ultrasound is the initial diagnostic modality of choice, though other modalities like CT angiog. and MRV may be necessary for certain CRT locations. Current guidelines recommend maintaining a catheter unless nonfunctional or unneeded, in addn. to systemic anticoagulation. Data guiding anticoagulant management specific to upper extremity VTE is lacking, and practice is mostly extrapolated from data on lower extremities. Further studies are required to establish evidence-based guidelines in the management of adults and children with CRT, and in particular the role of direct oral anticoagulants. In this review, we describe the knowledge gaps that exist in multiple aspects of CRT and the need for large collaborative studies to improve the care of patients with CRT.
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    Scharn, D. M.; Dirven, M.; Barendregt, W. B.; Boll, A. P.; Roelofs, D.; van der Vliet, J. A. Human umbilical vein versus heparin-bonded polyester for femoro-popliteal bypass: 5-year results of a prospective randomized multicentre trial. Eur. J. Vasc Endovasc Surg. 2008, 35 (1), 61– 7,  DOI: 10.1016/j.ejvs.2007.08.004
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    Camboni, D.; Philipp, A.; Arlt, M.; Pfeiffer, M.; Hilker, M.; Schmid, C. First Experience With a Paracorporeal Artificial Lung In Humans. ASAIO J. 2009, 55 (3), 304– 306,  DOI: 10.1097/MAT.0b013e31819740a0
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    Maul, T. M. ECMO Anticoagulation: It’s Still the Biggest Challenge; American Society of Artificial Internal Organs, 2015.
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    Demarest, C. T.; Shoemaker, S. J.; Chicotka, S. R. Clot Formation and Functional Changes in the CardioHelp Oxygenator Over Time. Abstract. ASAIO Journal 2016 Conference Abstracts 2016, 106
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    Hohlfelder, B.; Szumita, P. M.; Lagambina, S.; Weinhouse, G.; Degrado, JR Safety of Propofol for Oxygenator Exchange in Extracorporeal Membrane Oxygenation. ASAIO J. 2017, 63 (2), 179– 184,  DOI: 10.1097/MAT.0000000000000461
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    Philipp, A.; De Somer, F.; Foltan, M. Life span of different extracorporeal membrane systems for severe respiratory failure in the clinical practice. PLoS One. 2018, 13 (6), e0198392  DOI: 10.1371/journal.pone.0198392
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    Reser, D.; Seifert, B.; Klein, M. Retrospective analysis of outcome data with regards to the use of Phisio(R)-, Bioline(R)- or Softline(R)-coated cardiopulmonary bypass circuits in cardiac surgery. Perfusion. 2012, 27 (6), 530– 4,  DOI: 10.1177/0267659112454558
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    Sohn, N.; Marcoux, J.; Mycyk, T.; Krahn, J.; Meng, Q. The impact of different biocompatible coated cardiopulmonary bypass circuits on inflammatory response and oxidative stress. Perfusion. 2009, 24 (4), 231– 7,  DOI: 10.1177/0267659109351218
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    The impact of different biocompatible coated cardiopulmonary bypass circuits on inflammatory response and oxidative stress
    Sohn N; Marcoux J; Mycyk T; Krahn J; Meng Qh
    Perfusion (2009), 24 (4), 231-7 ISSN:.
    This study was to compare the impact of different biocompatible coated circuits on inflammatory response and oxidative stress induced during cardiopulmonary bypass (CPB). Seventy-eight patients undergoing elective coronary artery bypass grafting (CABG) with CPB were randomly assigned to five groups with different biocompatible coated circuits: Trillium, Bioline, Phosphorylcholine, Polymethoxyethyl acrylate (PMEA), and the uncoated control group. Blood was drawn at three different time points: before CPB, 6 and 72 hours post CPB. Unlike the Trillium group, serum levels of TNF-alpha in the Bioline and Phosphorylcholine groups significantly increased only at 72 hours post CPB (p < 0.05). Serum levels of IL-6 significantly increased at 6 and 72 hours post CPB in all groups (p < 0.01). The Trillium group showed a significant increase of IL-10 compared to the control group at 72 hours post CPB (p < 0.05). Serum levels of NOx in the Phosphorylcholine group significantly decreased at 6 hours post CPB compared to baseline (p < 0.05). Both the Bioline and Phosphorylcholine groups showed statistical decreases in serum NOx levels compared with other groups at 6 hours post CPB (p < 0.05). A significant difference in NOx levels between the Bioline and the control group was also observed at 72 hours post CPB. Myeloperoxidase levels were significantly elevated at 6 and 72 hours post CPB in all groups (p < 0.05). Inflammatory response and oxidative stress are elevated during CABG with CPB. Heparin-coated and the Phosphorylcholine-coated circuits induce less inflammatory responses and oxidative stress compared to other circuits.
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    Marcoux, J.; Sohn, N.; McNair, E. Outcomes comparison of 5 coated cardiopulmonary bypass circuits versus an uncoated control group of patients undergoing cardiac surgery. Perfusion. 2009, 24 (5), 307– 15,  DOI: 10.1177/0267659109352114
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    Outcomes comparison of 5 coated cardiopulmonary bypass circuits versus an uncoated control group of patients undergoing cardiac surgery
    Marcoux J; Sohn N; McNair E; Rosin M; Smith G; Lim H; Mycyk T; Meng Q
    Perfusion (2009), 24 (5), 307-15 ISSN:.
    UNLABELLED: Attenuated inflammatory response and decreased platelet activation have been claimed repeatedly when biocompatible circuits are used for cardiopulmonary bypass. We evaluated five Health Canada approved biocompatible circuit coatings (BCC) against an un-coated control group to determine their effectiveness in improving post-operative outcomes. Patients were assigned to the Control group or one of the 5 coated circuit groups: 40 Control; 33 Trillium; 32 Phisio; 34 Bioline; 33 X; and 11 GBS. Measured outcomes included: ventilator time; ICU time; post-operative chest tube drainage and transfusion volume; high sensitivity C-reactive protein (hsCRP); tau protein; and pre- and 72-hour post-operative anti-saccadic eye movement test comparisons. RESULTS: 183 patients were enlisted into the study. One arm of the study (GBS) was abandoned after 11 patients on account of inconsistent pressure excursions within the oxygenator and the excessive consumption of platelets necessitating transfusion. Patients in the X-coated group had significantly longer ventilator and intensive care unit (ICU) time compared to the three remaining coated circuit study groups. Though not significant, patients in the X group also demonstrated the highest post-operative chest tube losses, the most platelet transfusions, the highest tau protein levels and the lowest post-operative anti-saccadic eye movement test (ASEMT) results compared to the three remaining coated groups. The patients in the Trillium, Bioline and Phisio groups showed an improvement in ventilator and ICU time relative to the Control group. The diabetic patients in the Trillium, Bioline and Phisio groups showed an improvement in bleeding relative to the diabetic patients in the Control group. CONCLUSION: We compared all 5 coated circuits approved for clinical use in Canada against an uncoated control circuit. Three of the 5 coated circuits (Trillium, Phisio and Bioline BCC) were found to improve ventilator and ICU time compared to Control. Further studies are indicated to validate these results and their impact upon approval criteria, purchasing choices and safe clinical practice, especially as applied to higher risk diabetic patients.
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    Pieri, M.; Turla, O. G.; Calabro, M. G. A new phosphorylcholine-coated polymethylpentene oxygenator for extracorporeal membrane oxygenation: a preliminary experience. Perfusion. 2013, 28 (2), 132– 7,  DOI: 10.1177/0267659112469642
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    A new phosphorylcholine-coated polymethylpentene oxygenator for extracorporeal membrane oxygenation: a preliminary experience
    Pieri M; Turla O G; Calabro M G; Ruggeri L; Agracheva N; Zangrillo A; Pappalardo F
    Perfusion (2013), 28 (2), 132-7 ISSN:.
    Phosphorylcholine coating has a major role in the improvement of biocompatibility, durability and antihrombogenicity of the circuit for extracorporeal membrane oxygenation (ECMO). Moreover, if heparin-induced thrombocytopenia ensues, removal of all the sources of heparin is challenging if the circuit is coated with heparin. We report our preliminary experience with the new EUROSETS A.L.ONE ECMO oxygenator (Eurosets, Medolla, MO, Italy), which is aimed at providing better biocompatibility thanks to its full coating with phosphorylcholine. We retrospectively collected data on the 16 patients supported with ECMO and with the EUROSETS A.L.ONE ECMO oxygenator at San Raffaele Hospital. Mean ECMO duration was 6 ± 4 days, and 37.5% of the patients died on ECMO. Four episodes of major bleeding and three episodes of minor bleeding were recorded. The oxygenator had an excellent performance in gas exchange and the median pressure drop was 57 (26-85) mmHg at full blood flow (2.5 L/m2/min). The EUROSETS A.L.ONE ECMO oxygenator was an excellent device in our preliminary experience. Further evaluation on a larger sample is encouraged.
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    Amoako, K.; Kaufman, R.; Haddad, W. A. M. Zwitterionic Polysulfobetaine Coating and Antiplatelet Liposomes Reduce Fouling in Artificial Lung Circuits. Macromol. Biosci. 2023, 23 (4), 2200479,  DOI: 10.1002/mabi.202200479
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    Malkin, A. D.; Ye, S. H.; Lee, E. J. Development of zwitterionic sulfobetaine block copolymer conjugation strategies for reduced platelet deposition in respiratory assist devices. J. Biomed Mater. Res. B Appl. Biomater. 2018, 106 (7), 2681– 2692,  DOI: 10.1002/jbm.b.34085
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    Ye, S. H.; Arazawa, D. T.; Zhu, Y. Hollow fiber membrane modification with functional zwitterionic macromolecules for improved thromboresistance in artificial lungs. Langmuir. 2015, 31 (8), 2463– 71,  DOI: 10.1021/la504907m
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    Hollow Fiber Membrane Modification with Functional Zwitterionic Macromolecules for Improved Thromboresistance in Artificial Lungs
    Ye, Sang-Ho; Arazawa, David T.; Zhu, Yang; Shankarraman, Venkat; Malkin, Alexander D.; Kimmel, Jeremy D.; Gamble, Lara J.; Ishihara, Kazuhiko; Federspiel, William J.; Wagner, William R.
    Langmuir (2015), 31 (8), 2463-2471CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Respiratory assist devices seek optimized performance in terms of gas transfer efficiency and thromboresistance to minimize device size and reduce complications assocd. with inadequate blood biocompatibility. The exchange of gas with blood occurs at the surface of the hollow fiber membranes (HFMs) used in these devices. In this study, three zwitterionic macromols. were attached to HFM surfaces to putatively improve thromboresistance: (1) carboxyl-functionalized zwitterionic phosphorylcholine (PC) and (2) sulfobetaine (SB) macromols. (mPC or mSB-COOH) prepd. by a simple thiol-ene radical polymn. and (3) a low-mol. wt. sulfobetaine (SB)-co-methacrylic acid (MA) block copolymer (SBMAb-COOH) prepd. by reversible addn.-fragmentation chain transfer (RAFT) polymn. Each macromol. type was covalently immobilized on an aminated com. HFM (Celg-A) by a condensation reaction, and HFM surface compn. changes were analyzed by XPS. Thrombotic deposition on the HFMs was investigated after contact with ovine blood in vitro. The removal of CO2 by the HFMs was also evaluated using a model respiratory assistance device. The HFMs conjugated with zwitterionic macromols. (Celg-mPC, Celg-mSB, and Celg-SBMAb) showed expected increases in phosphorus or sulfur surface content. Celg-mPC and Celg-SBMAb experienced rates of platelet deposition significantly lower than those of unmodified (Celg-A, >95% redn.) and heparin-coated (>88% redn.) control HFMs. Smaller redns. were seen with Celg-mSB. The CO2 removal rate for Celg-SBMAb HFMs remained comparable to that of Celg-A. In contrast, the rate of removal of CO2 for heparin-coated HFMs was significantly reduced. The results demonstrate a promising approach to modifying HFMs using zwitterionic macromols. for artificial lung devices with improved thromboresistance without degrdn. of gas transfer.
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    Ye, S. H.; Orizondo, R. A.; De, B. N. Epoxy silane sulfobetaine block copolymers for simple, aqueous thromboresistant coating on ambulatory assist lung devices. J. Biomed Mater. Res. A 2024, 112 (1), 99– 109,  DOI: 10.1002/jbm.a.37619
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    Wang, Y.-B.; Gong, M.; Yang, S.; Nakashima, K.; Gong, Y.-K. Hemocompatibility and film stability improvement of crosslinkable MPC copolymer coated polypropylene hollow fiber membrane. J. Membr. Sci. 2014, 452, 29– 36,  DOI: 10.1016/j.memsci.2013.10.032
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    Hemocompatibility and film stability improvement of crosslinkable 2-methacryloyloxyethyl phosphorylcholine copolymer coated polypropylene hollow fiber membrane
    Wang, Yan-Bing; Gong, Ming; Yang, Shan; Nakashima, Kenichi; Gong, Yong-Kuan
    Journal of Membrane Science (2014), 452 (), 29-36CODEN: JMESDO; ISSN:0376-7388. (Elsevier B.V.)
    Hollow fiber membranes (HFMs) based artificial lungs require a large blood-contacting membrane surface area to provide adequate gas exchange. However, such a large surface presents significant challenges to hemocompatibility. For improving the hemocompatibility, amphiphilic and cell outer membrane mimetic 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers contg. 3-(Trimethoxysilyl)propyl methacrylate (TSMA) and/or Bu methacrylate (BMA) units, poly(MPC-co-BMA-co-TSMA) (PMBT) and poly(MPC-co-BMA) (PMB) were coated on a com. polypropylene (PP) HFM. Dynamic contact angle, ATR-FTIR and XPS results showed that both the PMB and PMBT phospholipid polymer coatings are stable in water, but only the crosslinked PMBT coating can resist the dissoln. by ethanol or SDS aq. soln. Protein adsorption, platelet adhesion and whole blood contact expts. showed significant improvement in hemocompatibility after being coated with the PMBT. Moreover, oxygenation expts. indicated that the blood compatible coating could resist blood permeance and did not hinder the gas exchange. Overall these findings revealed improved hemocompatibility which can be realized through crosslinkable phospholipid polymer coating, enabling more stable and more biocompatible HFMs respiratory assist devices.
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    Li, R.; Xu, J.; Li, Y. An endothelium membrane mimetic antithrombotic coating enables safer and longer extracorporeal membrane oxygenation application. Acta Biomater. 2024, 186, 185– 200,  DOI: 10.1016/j.actbio.2024.07.058
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    Xiang, T.; Lu, T.; Xie, Y.; Zhao, W. F.; Sun, S. D.; Zhao, C. S. Zwitterionic polymer functionalization of polysulfone membrane with improved antifouling property and blood compatibility by combination of ATRP and click chemistry. Acta Biomater. 2016, 40, 162– 171,  DOI: 10.1016/j.actbio.2016.03.044
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    Zwitterionic polymer functionalization of polysulfone membrane with improved antifouling property and blood compatibility by combination of ATRP and click chemistry
    Xiang, Tao; Lu, Ting; Xie, Yi; Zhao, Wei-Feng; Sun, Shu-Dong; Zhao, Chang-Sheng
    Acta Biomaterialia (2016), 40 (), 162-171CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    The chem. compns. are very important for designing blood-contacting membranes with good antifouling property and blood compatibility. In this study, we propose a method combining ATRP and click chem. to introduce zwitterionic polymer of poly(sulfobetaine methacrylate) (PSBMA), neg. charged polymers of poly(sodium methacrylate) (PNaMAA) and/or poly(sodium p-styrene sulfonate) (PNaSS), to improve the antifouling property and blood compatibility of polysulfone (PSf) membranes. Attenuated total reflectance-Fourier transform IR spectra, XPS and water contact angle results confirmed the successful grafting of the functional polymers. The antifouling property and blood compatibility of the modified membranes were systematically investigated. The zwitterionic polymer (PSBMA) grafted membranes showed good resistance to protein adsorption and bacterial adhesion; the neg. charged polymer (PNaSS or PNaMAA) grafted membranes showed improved blood compatibility, esp. the anticoagulant property. Moreover, the PSBMA/PNaMAA modified membrane showed both antifouling property and anticoagulant property, and exhibited a synergistic effect in inhibiting blood coagulation. The functionalization of membrane surfaces by a combination of ATRP and click chem. is demonstrated as an effective route to improve the antifouling property and blood compatibility of membranes in blood-contact.
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    Xie, Y.; Li, S. S.; Jiang, X.; Xiang, T.; Wang, R.; Zhao, C. S. Zwitterionic glycosyl modified polyethersulfone membranes with enhanced anti-fouling property and blood compatibility. J. Colloid Interface Sci. 2015, 443, 36– 44,  DOI: 10.1016/j.jcis.2014.11.053
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    101
    Zwitterionic glycosyl modified polyethersulfone membranes with enhanced anti-fouling property and blood compatibility
    Xie, Yi; Li, Shuang-Si; Jiang, Xin; Xiang, Tao; Wang, Rui; Zhao, Chang-Sheng
    Journal of Colloid and Interface Science (2015), 443 (), 36-44CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
    Novel zwitterionic glycosyl modified polyethersulfone (PES) ultrafiltration membranes were prepd. via in-situ crosslinking polymn. coupled with phase inversion technique, and the following reactions. The membranes were characterized by FTIR spectroscopy, TGA, SEM, 1H NMR spectrum, and static water contact angles (WCAs) measurements. The modified membranes showed excellent anti-fouling property, and the flux recovery ratio could reach almost 100%. Meanwhile, the blood compatibility of the membranes was measured by protein adsorption, platelet adhesion, activated partial thromboplastin time (APTT), and thrombin time (TT). The results implied that the zwitterionic glycosyl modified PES membranes had good anti-fouling property and blood compatibility.
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    Xiang, T.; Zhang, L. S.; Wang, R.; Xia, Y.; Su, B. H.; Zhao, C. S. Blood compatibility comparison for polysulfone membranes modified by grafting block and random zwitterionic copolymers via surface-initiated ATRP. J. Colloid Interface Sci. 2014, 432, 47– 56,  DOI: 10.1016/j.jcis.2014.06.044
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    102
    Blood compatibility comparison for polysulfone membranes modified by grafting block and random zwitterionic copolymers via surface-initiated ATRP
    Xiang, Tao; Zhang, Li-Sha; Wang, Rui; Xia, Yi; Su, Bai-Hai; Zhao, Chang-Sheng
    Journal of Colloid and Interface Science (2014), 432 (), 47-56CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
    For blood-contacting materials, good blood compatibility, esp. good anticoagulant property is of great importance. Zwitterionic polymers are resistant to nonspecific protein adsorption and platelet adhesion; however, their anticoagulant property is always inadequate. Two kinds of zwitterionic copolymers (sulfobetaine methacrylate and sodium p-styrene sulfonate random copolymer and block copolymer) with sulfonic groups were covalently grafted from polysulfone (PSf) membranes via surface-initiated atom transfer radical polymn. (SI-ATRP) to improve blood compatibility. Field emission SEM (FE-SEM), attenuated total reflectance-FTIR spectra (ATR-FTIR), XPS, and static water contact angle (WCA) were applied to characterize the morphologies, chem. compns. and hydrophilicity of the modified membranes. All the zwitterionic copolymer modified membranes showed improved blood compatibility, esp. the anticoagulant property was obviously enhanced compared to the pristine PSf and simple zwitterionic polymer modified membranes. Also the random copolymer modified membranes showed better resistance to platelet adhesion than the block copolymer modified membranes. The zwitterionic copolymer modified membranes with integrated antifouling property and blood compatibility provided wide choice for specific applications such as hemodialysis, hemofiltration, and plasma sepn.
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    Xiang, T.; Wang, R.; Zhao, W. F.; Sun, S. D.; Zhao, C. S. Covalent deposition of zwitterionic polymer and citric acid by click chemistry-enabled layer-by-layer assembly for improving the blood compatibility of polysulfone membrane. Langmuir. 2014, 30 (18), 5115– 25,  DOI: 10.1021/la5001705
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    103
    Covalent Deposition of Zwitterionic Polymer and Citric Acid by Click Chemistry-Enabled Layer-by-Layer Assembly for Improving the Blood Compatibility of Polysulfone Membrane
    Xiang, Tao; Wang, Rui; Zhao, Wei-Feng; Sun, Shu-Dong; Zhao, Chang-Sheng
    Langmuir (2014), 30 (18), 5115-5125CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Development of blood compatible membranes is crit. for biomedical applications. Zwitterionic polymers have been proved to be resistant to nonspecific protein adsorption and platelet adhesion. In this work, two kinds of zwitterionic copolymers bearing alkynyl and azide groups are synthesized by atom transfer radical polymn. (ATRP) and subsequent reactions, namely alkynyl-poly(sulfobetaine methacrylate) (alkynyl-PSBMA) and azide-poly(sulfobetaine methacrylate) (azide-PSBMA). The copolymers are directly used to modify azido-functionalized polysulfone (PSf-N3) membrane via click chem.-enabled layer-by-layer (LBL) assembly. Alkynyl-citric acid is then clicked onto the membrane when the outermost layer was azide-PSBMA. The chem. compns., surface morphologies, and hydrophilicity of the zwitterionic polymer and citric acid multilayer modified membranes are characterized. The composite multilayer is resistant to protein adsorption and platelet adhesion and also prolongs clotting times, indicating that the blood compatibility is improved. Moreover, after clicking the small mol. anticoagulant alkynyl-citric acid onto the outermost of the zwitterionic multilayer, the membrane shows further improved anticoagulant property. The deposition of zwitterionic polymer and citric acid via click chem.-enabled LBL assembly can improve the blood compatibility of the PSf membrane.
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    An, Z.; Dai, F.; Wei, C.; Zhao, Y.; Chen, L. Polydopamine/cysteine surface modified hemocompatible poly(vinylidene fluoride) hollow fiber membranes for hemodialysis. J. Biomed Mater. Res. B Appl. Biomater. 2018, 106 (8), 2869– 2877,  DOI: 10.1002/jbm.b.34106
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    Kensinger, C.; Karp, S.; Kant, R. First Implantation of Silicon Nanopore Membrane Hemofilters. ASAIO J. 2016, 62 (4), 491– 5,  DOI: 10.1097/MAT.0000000000000367
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    Kovach, K. M.; Capadona, J. R.; Gupta, A. S.; Potkay, J. A. The effects of PEG-based surface modification of PDMS microchannels on long-term hemocompatibility. J. Biomed Mater. Res. A 2014, 102 (12), 4195– 205,  DOI: 10.1002/jbm.a.35090
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    Plegue, T. J.; Kovach, K. M.; Thompson, A. J.; Potkay, J. A. Stability of Polyethylene Glycol and Zwitterionic Surface Modifications in PDMS Microfluidic Flow Chambers. Langmuir. 2018, 34 (1), 492– 502,  DOI: 10.1021/acs.langmuir.7b03095
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    Stability of Polyethylene Glycol and Zwitterionic Surface Modifications in PDMS Microfluidic Flow Chambers
    Plegue, Thomas J.; Kovach, Kyle M.; Thompson, Alex J.; Potkay, Joseph A.
    Langmuir (2018), 34 (1), 492-502CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Blood-material interactions are crucial to the lifetime, safety, and overall success of blood contacting devices. Hydrophilic polymer coatings have been employed to improve device lifetime by shielding blood contacting materials from the natural foreign body response, primarily the intrinsic pathway of the coagulation cascade. These coatings have the ability to repel proteins, cells, bacteria, and other microorganisms. Coatings are desired to have long-term stability, so that the nonthrombogenic and nonfouling effects gained are long lasting. Unfortunately, there exist limited studies which investigate their stability under dynamic flow conditions as encountered in a physiol. setting. In addn., direct comparisons between multiple coatings are lacking in the literature. In this study, we investigate the stability of polyethylene glycol (PEG), zwitterionic sulfobetaine silane (SBSi), and zwitterionic polyethylene glycol sulfobetaine silane (PEG-SBSi) grafted by a room temp., sequential flow chem. process on polydimethylsiloxane (PDMS) over time under ambient, static fluid (no flow), and physiol. relevant flow conditions and compare the results to uncoated PDMS controls. PEG, SBSi, and PEG-SBSi coatings maintained contact angles below 20° for up to 35 days under ambient conditions. SBSi and PEG-SBSi showed increased stability and hydrophilicity after 7 days under static conditions. They also retained contact angles ≤40° for all shear rates after 7 days under flow, demonstrating their potential for long-term stability. The effectiveness of the coatings to resist platelet adhesion was also studied under physiol. flow conditions. PEG showed a 69% redn. in adhered platelets, PEG-SBSi a significant 80% redn., and SBSi a significant 96% redn. compared to uncoated control samples, demonstrating their potential applicability for blood contacting applications. In addn., the presented coatings and their stability under shear may be of interest in other applications including marine coatings, lab. on a chip devices, and contact lenses, where it is desirable to reduce surface fouling due to proteins, cells, and other organisms.
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    Thompson, A. J.; Ma, L. J.; Major, T. Assessing and improving the biocompatibility of microfluidic artificial lungs. Acta Biomater. 2020, 112, 190– 201,  DOI: 10.1016/j.actbio.2020.05.008
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    Dabaghi, M.; Rochow, N.; Saraei, N. A Pumpless Microfluidic Neonatal Lung Assist Device for Support of Preterm Neonates in Respiratory Distress. Adv. Sci. (Weinh). 2020, 7 (21), 2001860,  DOI: 10.1002/advs.202001860
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    Isenberg, B. C.; Vedula, E. M.; Santos, J. A Clinical-Scale Microfluidic Respiratory Assist Device with 3D Branching Vascular Networks. Adv. Sci. (Weinh). 2023, 10 (18), e2207455  DOI: 10.1002/advs.202207455
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    Roberts, T. R.; Persello, A.; Harea, G. T. First 24-h-Long Intensive Care Unit Testing of a Clinical-Scale Microfluidic Oxygenator in Swine: A Safety and Feasibility Study. ASAIO J. 2024, 70 (6), 535– 544,  DOI: 10.1097/MAT.0000000000002127
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    Iqbal, Z.; Kim, S.; Moyer, J. In vitro and in vivo hemocompatibility assessment of ultrathin sulfobetaine polymer coatings for silicon-based implants. J. Biomater Appl. 2019, 34 (2), 297– 312,  DOI: 10.1177/0885328219831044
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    In vitro and in vivo hemocompatibility assessment of ultrathin sulfobetaine polymer coatings for silicon-based implants
    Iqbal, Zohora; Kim, Steven; Moyer, Jarrett; Moses, Willieford; Abada, Emily; Wright, Nathan; Kim, Eun Jung; Park, Jaehyun; Fissell, William H.; Vartanian, Shant; Roy, Shuvo
    Journal of Biomaterials Applications (2019), 34 (2), 297-312CODEN: JBAPEL; ISSN:0885-3282. (Sage Publications Ltd.)
    Highly uniform silicon nanopore membranes were developed for applications in implantable bioartificial organs. A robust, readily scalable, non-fouling surface coating is required to enhance silicon nanopore membrane hemocompatibility. However, the coating must be ultrathin to keep the nanopores from occluding. Recently, zwitterionic brush polymers have demonstrated significantly lower fouling under biol. conditions. In this study, we explore ultrathin zwitterionic poly(sulfobetaine methacrylate) (pSBMA) surface coating at sub-5 nm thickness. Membrane hydraulic permeability was measured before and after surface modification of silicon nanopore membranes, and pores were found to be patent and in agreement with coating thickness measurements. Coating stability was analyzed under biol. shear as well as under blood flow in vitro and in vivo. Following exposure to shear over 24 h, coatings were characterized via XPS, goniometry, and ellipsometry, and found to survive biol. shear. In vitro blood expts. with fresh human blood as well as in vivo 7-day and 26-day implants in a porcine model demonstrate minimal platelet adhesion and activation with pSBMA surface modification compared to unmodified silicon exposed to fresh human blood in vitro. These results demonstrate that ultrathin pSBMA surface modification is a viable choice for application in blood contacting implants with crit. nanoscale features.
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    Li, L.; Marchant, R. E.; Dubnisheva, A.; Roy, S.; Fissell, W. H. Anti-biofouling Sulfobetaine Polymer Thin Films on Silicon and Silicon Nanopore Membranes. J. Biomater Sci. Polym. Ed. 2011, 22 (1–3), 91– 106,  DOI: 10.1163/092050609X12578498982998
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    Anti-biofouling sulfobetaine polymer thin films on silicon and silicon nanopore membranes
    Li, Lingyan; Marchant, Roger E.; Dubnisheva, Anna; Roy, Shuvo; Fissell, William H.
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    Silicon nanopore membranes (SNM) with monodisperse pore size distributions have potential applications in bioartificial kidneys. A protein resistant thin film coating on the SNM is required to minimize biofouling and, hence, enhance the performance efficiency of SNM. A zwitterionic polymer, poly(sulfobetaine methacrylate) (polySBMA), was used to coat silicon and SNM substrates via a surface initiated atom transfer radical polymn. method. The polySBMA-coated surfaces were characterized using contact angle goniometry, XPS, ellipsometry and SEM. Resistance of the coatings to protein fouling was examd. by measurement of fibrinogen adsorption from fibrinogen soln. and human plasma on coated silicon surfaces. Results showed that the polySBMA coating suppresses non-specific adsorption of fibrinogen. The protein-repellent property of polySBMA thin film coating is comparable to that of PEG-based coatings. Anal. of the surfaces by XPS indicated that the films remained stable when stored under physiol. conditions over a 4-wk period.
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    Iqbal, Z.; Moses, W.; Kim, S.; Kim, E. J.; Fissell, W. H.; Roy, S. Sterilization effects on ultrathin film polymer coatings for silicon-based implantable medical devices. J. Biomed Mater. Res. B Appl. Biomater. 2018, 106 (6), 2327– 2336,  DOI: 10.1002/jbm.b.34039
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    Himmelfarb, J.; Ratner, B. Wearable artificial kidney: problems, progress and prospects. Nat. Rev. Nephrol. 2020, 16 (10), 558– 559,  DOI: 10.1038/s41581-020-0318-1
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    Wearable artificial kidney: problems, progress and prospects
    Himmelfarb Jonathan; Ratner Buddy
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    Starling, R. C.; Moazami, N.; Silvestry, S. C. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J. Med. 2014, 370 (1), 33– 40,  DOI: 10.1056/NEJMoa1313385
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    Mehra, M. R.; Goldstein, D. J.; Uriel, N. Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure. N Engl J. Med. 2018, 378 (15), 1386– 1395,  DOI: 10.1056/NEJMoa1800866
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    Kihara, S.; Yamazaki, K.; Litwak, K. N. In vivo evaluation of a MPC polymer coated continuous flow left ventricular assist system. Artif Organs. 2003, 27 (2), 188– 92,  DOI: 10.1046/j.1525-1594.2003.t01-2-06993.x
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    In vivo evaluation of a MPC polymer coated continuous flow left ventricular assist system
    Kihara Shin'ichiro; Yamazaki Kenji; Litwak Kenneth N; Litwak Philip; Kameneva Marina V; Ushiyama Hiroyuki; Tokuno Toshimasa; Borzelleca David C; Umezu Mitsuo; Tomioka Jun; Tagusari Osamu; Akimoto Takehide; Koyanagi Hitoshi; Kurosawa Hiromi; Kormos Robert L; Griffith Bartley P
    Artificial organs (2003), 27 (2), 188-92 ISSN:0160-564X.
    The aim of this study was the evaluation of the thrombogenicity and the biocompatibility of the SunMedical EVAHEART left ventricular assist system (LVAS) coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer compared to a diamond-like carbon (DLC) coating. Four calves were implanted with the MPC polymer-coated LVAS. Eight calves were implanted with DLC coated LVAS. The thrombogenicity and biocompatibility of the pumps were evaluated. At explant, 60.0 +/- 37.2% (5-85%) of the pump surface area was still coated with MPC polymer after the duration of 45.0 +/- 32.0 days. In 1 out of 4 MPC and 2 out of 8 DLC coated pumps, there was a very small amount of thrombus around the seal ring; otherwise the blood contacting surfaces were free of thrombus. Major organs were normal except for a few lesions in kidneys from both groups. The MPC polymer coated EVAHEART LVAS seems to have low thrombogenicity and high biocompatibility similar to the DLC coated system. The current study demonstrated that the MPC polymer coating shows great promise for being used as an antithrombogenic substrate for the LVAS due to its ease of application, significant cost benefit, and reduction in anticoagulation therapy in acute postoperative period.
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  • Abstract

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    Figure 1

    Figure 1. Clot formation in blood bearing medical devices: A) the large internal surface area of an oxygenator and its tubing fouled with blood clot; B) and C) clots on blood pumps; and D) and E) stopcocks and connectors occluded by blood clot.

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    Figure 2

    Figure 2. Select zwitterion side groups used as hydrophilic coatings.

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    Figure 3

    Figure 3. A) Schematic illustration of (left to right) a low-fouling conventional hydrogel showing protein entrapment and adhesion; a polymer brush surface coating, which highly resists nonspecific protein adsorption; and a low-fouling, lightly cross-linked hydrogel, which allows the free movement of proteins in and out of the hydrogel matrix without nonspecific protein adsorption. B) Preparation process of a glucose sensor coated with a pCBMA hydrogel lightly cross-linked with a CBMA cross-linker (CBMAX) and loaded with covalently immobilized GOx, leading to high GOx loading density, high glucose detection sensitivity, and very low nonspecific protein adsorption. C) Comparison of the experimental glucose sensor coated with 0.1% polyCBMA hydrogel with the Medtronic sensor in whole blood taken from rats, showing the blood glucose level is accurately measured by the uncoated, commercial sensor for less than 2 days and by the coated sensor for 42 days. D) Comparison of sensor sensitivity: blood glucose level is plotted as a function of PBS dilution. TMSPMA: 3-(trimethoxysilyl)propyl methacrylate. NHS/EDC: N-hydroxysuccinimide/1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. GOx: glucose oxidase. Adapted with permission from ref (58). Copyright 2012 Biomaterials.

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    Figure 4

    Figure 4. Achieving surface-focused anticoagulation in oxygenators using surface grafting with antifouling zwitterions conjugated with dopamine adhesive linkers. A) Coating of oxygenator fibers with dopamine-zwitterion (DOPA-zwitter) grafts using a wash through approach. B) Dopamine-polycarboxybetaine methacrylate (DOPA-pCBMA) and C) Dopamine-polysulfobetaine methacrylate (DOPA-pSBMA) were synthesized via solution atomic transfer radical polymerization. The reaction sequence starts with the reaction of dopamine (DOPA) linker with 2-bromoisobutyl bromide (Br-i-Bu-Br) initiator to form DOPA-Br and then the reaction of DOPA-Br with polycarboxybetaine methacrylate (CBMA) or polysulfobetaine methacrylate (SBMA) for form DOPA-pCBMA or DOPA-pSBMA. The substrate’s surface modification with DOPA-pCB polymer via pseudo one step “graft-to” coating approach was then applied. 1:6 free DOPA to DOPA-pCB were blended into a 2.5 mg/mL in tris(hydroxymethyl)aminomethane (TRIS) buffer (pH = 8.5) and was used to bathe substrates for 6 h.

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    Figure 5

    Figure 5. Artificial lung coating via pCBMA using a 4-DOPA attachment method (A) and resulting in vivo, artificial lung blood flow resistance vs time (B) demonstrating reduced clot formation leading to lower blood flow resistance over 36 h. Adapted with permission from ref (44). Copyright 2019 ACTA Biomaterialia.

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      Blood contact with high surface area medical devices, such as dialysis and extracorporeal life support (ECLS), induces rapid surface coagulation. Systemic anticoagulation, such as heparin, is thus necessary to slow clot formation, but some patients suffer from bleeding complications. Both problems might be reduced by 1) replacing heparin anticoagulation with artificial surface inhibition of the protein adsorption that initiates coagulation and 2) selective inhibition of the intrinsic branch of the coagulation cascade. This approach was evaluated by comparing clot formation and bleeding times during short-term ECLS using zwitterionic polycarboxybetaine (PCB) surface coatings combined with either a potent, selective, bicyclic peptide inhibitor of activated Factor XII (FXII900) or std. heparin anticoagulation. Rabbits underwent venovenous ECLS with small sham oxygenators for 60 min using three means of anticoagulation (n = 4 ea): (1) PCB coating + FXII900 infusion, (2) PCB coating + heparin infusion with an activated clotting time of 220-300s, and (3) heparin infusion alone. Sham oxygenator blood clot wts. in the PCB + FXII900 and PCB + heparin groups were 4% and 25% of that in the heparin group (p < 10-6 and p < 10-5), resp. At the same time, the bleeding time remained normal in the PCB + FXII900 group (2.4 ± 0.2 min) but increased to 4.8 ± 0.5 and 5.1 ± 0.7 min in the PCB + heparin and heparin alone groups (p < 10-4 and 0.01). Sham oxygenator blood flow resistance was significantly lower in the PCB + FXII900 and PCB + heparin groups than in the heparin only group (p < 10-6 and 10-5). These results were confirmed by gross and SEM (SEM) images and fibrinopeptide A (FPA) concns. Thus, the combined use of PCB coating and FXII900 markedly reduced sham oxygenator coagulation and tissue bleeding times vs. the clin. std. of heparin anticoagulation and is a promising anticoagulation method for clin. ECLS.
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      Yang, Rong; Gleason, Karen K.
      Langmuir (2012), 28 (33), 12266-12274CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Antifouling thin films of poly[N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)-co-2-(dimethylamino)ethyl methacrylate-co-ethylene glycol dimethacrylate] (PDDE) were synthesized via a substrate-independent and all-dry-initiated chem. vapor deposition (iCVD) technique followed by a diffusion-limited vapor-phase reaction with 1,3-propane sultone. Coated surfaces exhibited very low absorption of various foulants including bovine serum albumin (BSA), humic acid (HA), and sodium alginate (SA), as measured with the quartz crystal microbalance with dissipation monitoring (QCM-D). The fouling by humic acid was dependent on the presence of divalent cations such as Ca2+. Both depth profiling and angle-resolved XPS measurements indicated that the zwitterionic groups were highly concd. in the top ∼3 nm of the film. The contact angle measurements revealed a limited degree of surface chain reorganization upon contacting water. The dynamic contact angles remained unchanged after 100 days of storage in air, indicating the stability of the interface. The coating was substrate-independent, and the film was conformal on surface nanostructures including trenches, reverse osmosis membranes, and electrospun nanofiber mats.
    33. 33
      Peng, Y.; Peng, J.; Wang, Z.; Xiao, Y.; Qiu, X. Diamond-like Carbon Coatings in the Biomedical Field: Properties, Applications and Future Development. Coatings. 2022, 12 (8), 1088,  DOI: 10.3390/coatings12081088
      There is no corresponding record for this reference.
    34. 34
      Asatekin, A.; Barr, M. C.; Baxamusa, S. H. Designing polymer surfaces via vapor deposition. Materials Today. 2010, 13 (5), 26– 33,  DOI: 10.1016/S1369-7021(10)70081-X
      34
      Designing polymer surfaces via vapor deposition
      Asatekin, Ayse; Barr, Miles C.; Baxamusa, Salmaan H.; Lau, Kenneth K. S.; Tenhaeff, Wyatt; Xu, Jingjing; Gleason, Karen K.
      Materials Today (Oxford, United Kingdom) (2010), 13 (5), 26-33CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)
      A review. Chem. Vapor Deposition [CVD] methods significantly augment the capabilities of traditional surface modification techniques for designing polymeric surfaces. In CVD polymn., the monomer(s) are delivered to the surface through the vapor phase and then undergo simultaneous polymn. and thin film formation. By eliminating the need to dissolve macromols., CVD enables insol. polymers to be coated and prevents solvent damage to the substrate. Since de-wetting and surface tension effects are absent, CVD coatings conform to the geometry of the underlying substrate. Hence, CVD polymers can be readily applied to virtually any substrate: org., inorg., rigid, flexible, planar, three-dimensional, dense, or porous. CVD methods integrate readily with other vacuum processes used to fabricate patterned surfaces and devices. CVD film growth proceeds from the substrate up, allowing for interfacial engineering, real-time monitoring, thickness control, and the synthesis of films with graded compn. This article focuses on two CVD polymn. methods that closely translate soln. chem. to vapor deposition; initiated CVD and oxidative CVD. The basic concepts underlying these methods and the resultant advantages over other thin film coating techniques are described, along with selected applications where CVD polymers are an enabling technol.
    35. 35
      Roy, R. K.; Lee, K.-R. Biomedical applications of diamond-like carbon coatings: A review. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2007, 83B (1), 72– 84,  DOI: 10.1002/jbm.b.30768
      There is no corresponding record for this reference.
    36. 36
      Balikci, E.; Yilmaz, B.; Tahmasebifar, A.; Baran, E. T.; Kara, E. Surface modification strategies for hemodialysis catheters to prevent catheter-related infections: A review. J. Biomed Mater. Res. B Appl. Biomater. 2021, 109 (3), 314– 327,  DOI: 10.1002/jbm.b.34701
      There is no corresponding record for this reference.
    37. 37
      Srisang, S.; Nasongkla, N. Layer-by-layer dip coating of Foley urinary catheters by chlorhexidine-loaded micelles. Journal of Drug Delivery Science and Technology. 2019, 49, 235– 242,  DOI: 10.1016/j.jddst.2018.11.019
      There is no corresponding record for this reference.
    38. 38
      Love, J. C.; Estroff, L. A.; Kriebel, J. K.; Nuzzo, R. G.; Whitesides, G. M. Self-assembled monolayers of thiolates on metals as a form of nanotechnology. Chem. Rev. 2005, 105 (4), 1103– 69,  DOI: 10.1021/cr0300789
      38
      Self-Assembled Monolayers of Thiolates on Metals as a Form of Nanotechnology
      Love, J. Christopher; Estroff, Lara A.; Kriebel, Jennah K.; Nuzzo, Ralph G.; Whitesides, George M.
      Chemical Reviews (Washington, DC, United States) (2005), 105 (4), 1103-1169CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This article presents the complete review on the formation, structure, property, and potential application of self-assembled monolayer of thiolate on metal surface.
    39. 39
      Ulman, A. Formation and Structure of Self-Assembled Monolayers. Chem. Rev. 1996, 96 (4), 1533– 1554,  DOI: 10.1021/cr9502357
      39
      Formation and Structure of Self-Assembled Monolayers
      Ulman, Abraham
      Chemical Reviews (Washington, D. C.) (1996), 96 (4), 1533-1554CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review on the organization of complex, semiflexible org. mols. within quasi-2-D assemblies due to the delicate interplay between substrate-adsorbate interactions, nonbonded interactions between adsorbates, electrostatic and VDW forces, and intramol. interactions (e.g., bond stretches, angle bends, and torsions). Surface reorganization contributes to the final equil. structure of the assembly. Structural factors controlling the formation of self-assembled monolayers (SAMs) are discussed. Different SAMs with unique properties and potential applications are considered. An attempt is made to provide a general picture of self-assembly on solid surfaces as it emerges from a consideration of the interplay of different forces that control this process. 273 Refs.
    40. 40
      Alarfaj, A. A.; Lee, HH-c; Munusamy, M. A. Development of biomaterial surfaces with and without microbial nanosegments. Journal of Polymer Engineering. 2016, 36 (1), 1– 12,  DOI: 10.1515/polyeng-2015-0046
      There is no corresponding record for this reference.
    41. 41
      Amoako, K. A.; Sundaram, H. S.; Suhaib, A.; Jiang, S. Y.; Cook, K. E. Multimodal, Biomaterial-Focused Anticoagulation via Superlow Fouling Zwitterionic Functional Groups Coupled with Anti-Platelet Nitric Oxide Release. Advanced Materials Interfaces. 2016, 3 (6), 1500646,  DOI: 10.1002/admi.201500646
      There is no corresponding record for this reference.
    42. 42
      Hong, D.; Hung, H. C.; Wu, K. Achieving Ultralow Fouling under Ambient Conditions via Surface-Initiated ARGET ATRP of Carboxybetaine. ACS Appl. Mater. Interfaces. 2017, 9 (11), 9255– 9259,  DOI: 10.1021/acsami.7b01530
      42
      Achieving Ultralow Fouling under Ambient Conditions via Surface-Initiated ARGET ATRP of Carboxybetaine
      Hong, Daewha; Hung, Hsiang-Chieh; Wu, Kan; Lin, Xiaojie; Sun, Fang; Zhang, Peng; Liu, Sijun; Cook, Keith E.; Jiang, Shaoyi
      ACS Applied Materials & Interfaces (2017), 9 (11), 9255-9259CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      We achieved ultralow fouling on target surfaces by controlled polymn. of carboxybetaine under ambient conditions. The polymn. process for grafting polymer films onto the surfaces was carried out in air and did not require any deoxygenation step or specialized equipment. This method allows one to conveniently introduce a nonfouling polymer network onto large substrates.
    43. 43
      Sundaram, H. S.; Han, X.; Nowinski, A. K. Achieving One-step Surface Coating of Highly Hydrophilic Poly(Carboxybetaine Methacrylate) Polymers on Hydrophobic and Hydrophilic Surfaces. Adv. Mater. Interfaces. 2014, 1 (6), 1400071,  DOI: 10.1002/admi.201400071
      There is no corresponding record for this reference.
    44. 44
      Ukita, R.; Wu, K.; Lin, X. Zwitterionic poly-carboxybetaine coating reduces artificial lung thrombosis in sheep and rabbits. Acta Biomater. 2019, 92, 71– 81,  DOI: 10.1016/j.actbio.2019.05.019
      44
      Zwitterionic poly-carboxybetaine coating reduces artificial lung thrombosis in sheep and rabbits
      Ukita, Rei; Wu, Kan; Lin, Xiaojie; Carleton, Neil M.; Naito, Noritsugu; Lai, Angela; Do-Nguyen, Chi Chi; Demarest, Caitlin T.; Jiang, Shaoyi; Cook, Keith E.
      Acta Biomaterialia (2019), 92 (), 71-81CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Current artificial lungs fail in 1-4 wk due to surface-induced thrombosis. Biomaterial coatings may be applied to anticoagulate artificial surfaces, but none have shown marked long-term effectiveness. Poly-carboxybetaine (pCB) coatings have shown promising results in reducing protein and platelet-fouling in vitro. However, in vivo hemocompatibility remains to be investigated. Thus, three different pCB-grafting approaches to artificial lung surfaces were first investigated: 1) graft-to approach using 3,4-dihydroxyphenylalanine (DOPA) conjugated with pCB (DOPA-pCB); 2) graft-from approach using the Activators ReGenerated by Electron Transfer method of atom transfer radical polymn. (ARGET-ATRP); and 3) graft-to approach using pCB randomly copolymd. with hydrophobic moieties. One device coated with each of these methods and one uncoated device were attached in parallel within a veno-venous sheep extracorporeal circuit with no continuous anticoagulation (N = 5 circuits). The DOPA-pCB approach showed the least increase in blood flow resistance and the lowest incidence of device failure over 36-h. Next, we further investigated the impact of tip-to-tip DOPA-pCB coating in a 4-h rabbit study with veno-venous micro-artificial lung circuit at a higher activated clotting time of 220-300 s (N ≥ 5). Here, DOPA-pCB reduced fibrin formation (p = 0.06) and gross thrombus formation by 59% (p < 0.05). Therefore, DOPA-pCB is a promising material for improving the anticoagulation of artificial lungs. Chronic lung diseases lead to 168,000 deaths each year in America, but only 2300 lung transplantations happen each year. Hollow fiber membrane oxygenators are clin. used as artificial lungs to provide respiratory support for patients, but their long-term viability is hindered by surface-induced clot formation that leads to premature device failure. Among different coatings investigated for blood-contacting applications, poly-carboxybetaine (pCB) coatings have shown remarkable redn. in protein adsorption in vitro. However, their efficacy in vivo remains unclear. This is the first work that investigates various pCB-coating methods on artificial lung surfaces and their biocompatibility in sheep and rabbit studies. This work highlights the promise of applying pCB coatings on artificial lungs to extend its durability and enable long-term respiratory support for lung disease patients.
    45. 45
      Hong, Y.; Ye, S. H.; Nieponice, A.; Soletti, L.; Vorp, D. A.; Wagner, W. R. A small diameter, fibrous vascular conduit generated from a poly(ester urethane)urea and phospholipid polymer blend. Biomaterials. 2009, 30 (13), 2457– 67,  DOI: 10.1016/j.biomaterials.2009.01.013
      45
      A small diameter, fibrous vascular conduit generated from a poly(ester urethane)urea and phospholipid polymer blend
      Hong, Yi; Ye, Sang-Ho; Nieponice, Alejandro; Soletti, Lorenzo; Vorp, David A.; Wagner, William R.
      Biomaterials (2009), 30 (13), 2457-2467CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      The thrombotic and hyperplastic limitations assocd. with synthetic small diam. vascular grafts have generated sustained interest in finding a tissue engineering soln. for autologous vascular segment generation in situ. One approach is to place a biodegradable scaffold at the site that would provide acute mech. support while vascular tissue develops. To generate a scaffold that possessed both non-thrombogenic character and mech. properties appropriate for vascular tissue, a biodegradable poly(ester urethane)urea (PEUU) and non-thrombogenic bioinspired phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine-co-methacryloyloxyethyl butylurethane) (PMBU) were blended at PMBU wt. fractions of 0-15% and electrospun to create fibrous scaffolds. The composite scaffolds were flexible with breaking strains exceeding 300%, tensile strengths of 7-10 MPa and compliances of 2.9-4.4 × 10-4 mmHg-1. In vitro platelet deposition on the scaffold surfaces significantly decreased with increasing PMBU content. Rat smooth muscle cell proliferation was also inhibited on PEUU/PMBU blended scaffolds with greater inhibition at higher PMBU content. Fibrous vascular conduits (1.3 mm inner diam.) implanted in the rat abdominal aorta for 8 wk showed greater patency for grafts with 15% PMBU blending vs. PEUU without PMBU (67% vs. 40%). A thin neo-intimal layer with endothelial coverage and good anastomotic tissue integration was seen for the PEUU/PMBU vascular grafts. These results are encouraging for further evaluation of this technique in larger diam. applications for longer implant periods.
    46. 46
      Wang, L.; Miao, C.; Liang, F. Hydrogen sulfide releasing and carboxybetaine modified vascular graft with enhanced anticoagulant, anticalcification, and pro-endothelialization properties. Applied Materials Today. 2023, 35, 101976,  DOI: 10.1016/j.apmt.2023.101976
      There is no corresponding record for this reference.
    47. 47
      Ye, S. H.; Hong, Y.; Sakaguchi, H. Nonthrombogenic, biodegradable elastomeric polyurethanes with variable sulfobetaine content. ACS Appl. Mater. Interfaces. 2014, 6 (24), 22796– 806,  DOI: 10.1021/am506998s
      47
      Nonthrombogenic, Biodegradable Elastomeric Polyurethanes with Variable Sulfobetaine Content
      Ye, Sang-Ho; Hong, Yi; Sakaguchi, Hirokazu; Shankarraman, Venkat; Luketich, Samuel K.; D'Amore, Antonio; Wagner, William R.
      ACS Applied Materials & Interfaces (2014), 6 (24), 22796-22806CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      For applications where degradable polymers are likely to have extended blood contact, it is often important for these materials to exhibit high levels of thromboresistance. This can be achieved with surface modification approaches, but such modifications may be transient with degrdn. Alternatively, polymer design can be altered such that the bulk polymer is thromboresistant and this is maintained with degrdn. Toward this end a series of biodegradable, elastic polyurethanes (PESBUUs) contg. different zwitterionic sulfobetaine (SB) content were synthesized from a polycaprolactone-diol (PCL-diol):SB-diol mixt. (100:0, 75:25, 50:50, 25:75 and 0:100) reacted with diisocyanatobutane and chain extended with putrescine. The chem. structure, tensile mech. properties, thermal properties, hydrophilicity, biodegradability, fibrinogen adsorption and thrombogenicity of the resulting polymers was characterized. With increased SB content some weakening in tensile properties occurred in wet conditions and enzymic degrdn. also decreased. However, at higher zwitterionic molar ratios (50% and 75%) wet tensile strength exceeded 15 MPa and breaking strain was >500%. Markedly reduced thrombotic deposition was obsd. both before and after substantial degrdn. for both of these PESBUUs and they could be processed by electrospinning into a vascular conduit format with appropriate compliance properties. The mech. and degrdn. properties as well as the acute in vitro thrombogenicity assessment suggest that these tunable polyurethanes could provide options appropriate for use in blood contacting applications where a degradable, elastomeric component with enduring thromboresistance is desired.
    48. 48
      Yoneyama, T.; Ishihara, K.; Nakabayashi, N.; Ito, M.; Mishima, Y. Short-term in vivo evaluation of small-diameter vascular prosthesis composed of segmented poly(etherurethane)/2-methacryloyloxyethyl phosphorylcholine polymer blend. J. Biomed Mater. Res. 1998, 43 (1), 15– 20,  DOI: 10.1002/(SICI)1097-4636(199821)43:1<15::AID-JBM2>3.0.CO;2-P
      There is no corresponding record for this reference.
    49. 49
      Yoneyama, T.; Sugihara, K.; Ishihara, K.; Iwasaki, Y.; Nakabayashi, N. The vascular prosthesis without pseudointima prepared by antithrombogenic phospholipid polymer. Biomaterials. 2002, 23 (6), 1455– 9,  DOI: 10.1016/S0142-9612(01)00268-X
      There is no corresponding record for this reference.
    50. 50
      Yuan, Y.; Ai, F.; Zang, X.; Zhuang, W.; Shen, J.; Lin, S. Polyurethane vascular catheter surface grafted with zwitterionic sulfobetaine monomer activated by ozone. Colloids Surf. B Biointerfaces. 2004, 35 (1), 1– 5,  DOI: 10.1016/j.colsurfb.2004.01.005
      There is no corresponding record for this reference.
    51. 51
      Soletti, L.; Nieponice, A.; Hong, Y. In vivo performance of a phospholipid-coated bioerodable elastomeric graft for small-diameter vascular applications. J. Biomed Mater. Res. A 2011, 96 (2), 436– 448,  DOI: 10.1002/jbm.a.32997
      51
      In vivo performance of a phospholipid-coated bioerodable elastomeric graft for small-diameter vascular applications
      Soletti, Lorenzo; Nieponice, Alejandro; Hong, Yi; Ye, Sang-Ho; Stankus, John J.; Wagner, William R.; Vorp, David A.
      Journal of Biomedical Materials Research, Part A (2011), 96A (2), 436-448CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)
      There remains a great need for vascular substitutes for small-diam. applications. The use of an elastomeric biodegradable material, enabling acute antithrombogenicity and long-term in vivo remodeling, could be beneficial for this purpose. Conduits (1.3 mm internal diam.) were obtained by electrospinning biodegradable poly(ester urethane)urea (PEUU), and by luminally immobilizing a non-thrombogenic, 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymer. Platelet adhesion was characterized in vitro after contact with ovine blood. The conduits were implanted as aortic interposition grafts in the rat for 4, 8, 12, and 24 wk. Surface treatment resulted in a 10-fold decrease in platelet adhesion compared to untreated material. Patency at 8 wk was 92% for the coated grafts compared to 40% for the non-coated grafts. Histol. at 8 and 12 wk demonstrated formation of cellularized neotissue consisting of aligned collagen and elastin. The lumen of the grafts was confluent with cells qual. aligned in the direction of blood flow. Immunohistochem. suggested the presence of smooth muscle cells in the medial layer of the neotissue and endothelial cells lining the lumen. Mech., the grafts were less compliant than rat aortas prior to implantation (4.5 ± 2.0 × 10-4 mmHg-1 vs. 14.2 ± 1.1 × 10-4 mmHg-1, resp.), then after 4 wk in vivo they approximated native values, but subsequently became stiffer again at later time points. The novel coated grafts exhibited promising antithrombogenic and mech. properties for small-diam. arterial revascularization. Further evaluation in vivo will be required to demonstrate complete remodeling of the graft into a native-like artery. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011.
    52. 52
      Hou, Z.; Wu, Y.; Xu, C. Precisely Structured Nitric-Oxide-Releasing Copolymer Brush Defeats Broad-Spectrum Catheter-Associated Biofilm Infections In Vivo. ACS Cent Sci. 2020, 6 (11), 2031– 2045,  DOI: 10.1021/acscentsci.0c00755
      52
      Precisely Structured Nitric-Oxide-Releasing Copolymer Brush Defeats Broad-Spectrum Catheter-Associated Biofilm Infections In Vivo
      Hou, Zheng; Wu, Yang; Xu, Chen; Reghu, Sheethal; Shang, Zifang; Chen, Jingjie; Pranantyo, Dicky; Marimuth, Kalisvar; De, Partha Pratim; Ng, Oon Tek; Pethe, Kevin; Kang, En-Tang; Li, Peng; Chan-Park, Mary B.
      ACS Central Science (2020), 6 (11), 2031-2045CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Gram-neg. bacteria cannot be easily eradicated by antibiotics and are a major source of recalcitrant infections of indwelling medical devices. Among various device-assocd. infections, intravascular catheter infection is a leading cause of mortality. Prior approaches to surface modification, such as antibiotics impregnation, hydrophilization, unstructured NO-releasing, etc., have failed to achieve adequate infection-resistant coatings. We report a precision-structured diblock copolymer brush (H(N)-b-S) composed of a surface antifouling block of poly(sulfobetaine methacrylate) (S) and a subsurface bactericidal block (H(N)) of nitric-oxide-emitting functionalized poly(hydroxyethyl methacrylate) (H) covalently grafted from the inner and outer surfaces of a polyurethane catheter. The block copolymer architecture of the coating is important for achieving good broad-spectrum anti-biofilm activity with good biocompatibility and low fouling. The coating procedure is scalable to clin. useful catheter lengths. Only the block copolymer brush coating ((H(N)-b-S)) shows unprecedented, above 99.99%, in vitro biofilm inhibition of Gram-pos. and Gram-neg. bacteria, 100-fold better than previous coatings. It has negligible toxicity toward mammalian cells and excellent blood compatibility. In a murine s.c. infection model, it achieves >99.99% biofilm redn. of Gram-pos. and Gram-neg. bacteria compared with <90% for silver catheter, while in a porcine central venous catheter infection model, it achieves >99.99% redn. of MRSA with 5-day implantation. This precision coating is readily applicable for long-term biofilm-resistant and blood-compatible copolymer coatings covalently grafted from a wide range of medical devices. We report a precisely structured anti-infective polymer brush coating on a catheter that defeats biofilms of Gram-pos. and Gram-neg. bacteria with good hemo- and biocompatibility and is thrombus- and protein-resistant.
    53. 53
      Li, K.; Peng, J.; Liu, Y. Surface Engineering of Central Venous Catheters via Combination of Antibacterial Endothelium-Mimicking Function and Fibrinolytic Activity for Combating Blood Stream Infection and Thrombosis. Adv. Healthc Mater. 2023, 12 (23), e2300120  DOI: 10.1002/adhm.202300120
      There is no corresponding record for this reference.
    54. 54
      Singha, P.; Goudie, M. J.; Liu, Q. Multipronged Approach to Combat Catheter-Associated Infections and Thrombosis by Combining Nitric Oxide and a Polyzwitterion: a 7 Day In Vivo Study in a Rabbit Model. ACS Appl. Mater. Interfaces. 2020, 12 (8), 9070– 9079,  DOI: 10.1021/acsami.9b22442
      54
      Multipronged approach to combat catheter-associated infections and thrombosis by combining nitric oxide and a polyzwitterion: a 7 day in vivo study in a rabbit model
      Singha, Priyadarshini; Goudie, Marcus J.; Liu, Qiaohong; Hopkins, Sean; Brown, Nettie; Schmiedt, Chad W.; Locklin, Jason; Handa, Hitesh
      ACS Applied Materials & Interfaces (2020), 12 (8), 9070-9079CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      The development of nonfouling and antimicrobial materials has shown great promise for reducing thrombosis and infection assocd. with medical devices with aims of improving device safety and decreasing the frequency of antibiotic administration. Here, the design of an antimicrobial, anti-inflammatory, and antithrombotic vascular catheter is assessed in vivo over 7 d in a rabbit model. Antimicrobial and antithrombotic activity is achieved through the integration of a nitric oxide donor, while the nonfouling surface is achieved using a covalently bound phosphorylcholine-based polyzwitterionic copolymer topcoat. The effect of sterilization on the nonfouling nature and nitric oxide release is presented. The catheters reduced viability of Staphylococcus aureus in long-term studies (7 d in a CDC bioreactor) and inflammation in the 7 d rabbit model. Overall, this approach provides a robust method for decreasing thrombosis, inflammation, and infections assocd. with vascular catheters.
    55. 55
      Smith, R. S.; Zhang, Z.; Bouchard, M. Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. Sci. Transl Med. 2012, 4 (153), 153ra132,  DOI: 10.1126/scitranslmed.3004120
      There is no corresponding record for this reference.
    56. 56
      Gokaltun, A. A.; Mazzaferro, L.; Yarmush, M. L.; Usta, O. B.; Asatekin, A. Surface-segregating zwitterionic copolymers to control poly(dimethylsiloxane) surface chemistry. J. Mater. Chem. B 2023, 12 (1), 145– 157,  DOI: 10.1039/D3TB02164E
      There is no corresponding record for this reference.
    57. 57
      Mercader, A.; Ye, S. H.; Kim, S.; Orizondo, R. A.; Cho, S. K.; Wagner, W. R. PDMS-Zwitterionic Hybrid for Facile, Antifouling Microfluidic Device Fabrication. Langmuir. 2022, 38 (12), 3775– 3784,  DOI: 10.1021/acs.langmuir.1c03375
      There is no corresponding record for this reference.
    58. 58
      Yang, W.; Bai, T.; Carr, L. R. The effect of lightly crosslinked poly (carboxybetaine) hydrogel coating on the performance of sensors in whole blood. Biomaterials. 2012, 33 (32), 7945– 7951,  DOI: 10.1016/j.biomaterials.2012.07.035
      There is no corresponding record for this reference.
    59. 59
      Xie, X.; Doloff, J. C.; Yesilyurt, V. Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer. Nat. Biomed Eng. 2018, 2 (12), 894– 906,  DOI: 10.1038/s41551-018-0273-3
      59
      Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer
      Xie, Xi; Doloff, Joshua C.; Yesilyurt, Volkan; Sadraei, Atieh; McGarrigle, James J.; Omami, Mustafa; Veiseh, Omid; Farah, Shady; Isa, Douglas; Ghani, Sofia; Joshi, Ira; Vegas, Arturo; Li, Jie; Wang, Weiheng; Bader, Andrew; Tam, Hok Hei; Tao, Jun; Chen, Hui-jiuan; Yang, Boru; Williamson, Katrina Ann; Oberholzer, Jose; Langer, Robert; Anderson, Daniel G.
      Nature Biomedical Engineering (2018), 2 (12), 894-906CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)
      Continuous glucose monitors (CGMs), used by patients with diabetes mellitus, can autonomously track fluctuations in blood glucose over time. However, the signal produced by CGMs during the initial recording period following sensor implantation contains substantial noise, requiring frequent recalibration via finger-prick tests. Here, we show that coating the sensor with a zwitterionic polymer, found via a combinatorial chem. approach, significantly reduces signal noise and improves CGM performance. We evaluated the polymer-coated sensors in mice as well as in healthy and diabetic non-human primates, and show that the sensors accurately record glucose levels without the need for recalibration. We also show that the coated sensors significantly abrogated immune responses, as indicated by histol., fluorescent whole-body imaging of inflammation-assocd. protease activity and gene expression of inflammation markers. The polymer coating may allow CGMs to become standalone measuring devices.
    60. 60
      Jiang, S.; Cao, Z. Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv. Mater. 2010, 22 (9), 920– 32,  DOI: 10.1002/adma.200901407
      60
      Ultralow-Fouling, Functionalizable, and Hydrolyzable Zwitterionic Materials and Their Derivatives for Biological Applications
      Jiang, Shaoyi; Cao, Zhiqiang
      Advanced Materials (Weinheim, Germany) (2010), 22 (9), 920-932CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. In recent years, zwitterionic materials such as poly(carboxybetaine) (pCB) and poly(sulfobetaine) (pSB) have been applied to a broad range of biomedical and engineering materials. Due to electrostatically induced hydration, surfaces coated with zwitterionic groups are highly resistant to nonspecific protein adsorption, bacterial adhesion, and biofilm formation. Among zwitterionic materials, pCB is unique due to its abundant functional groups for the convenient immobilization of biomols. pCB can also be prepd. in a hydrolyzable form as cationic pCB esters, which can kill bacteria or condense DNA. The hydrolysis of cationic pCB esters into nonfouling zwitterionic groups will lead to the release of killed microbes or the irreversible unpackaging of DNA. Furthermore, mixed-charge materials have been shown to be equiv. to zwitterionic materials in resisting nonspecific protein adsorption when they are uniformly mixed at the mol. scale.
    61. 61
      Keefe, A. J.; Jiang, S. Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity. Nat. Chem. 2012, 4 (1), 59– 63,  DOI: 10.1038/nchem.1213
      61
      Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity
      Keefe, Andrew J.; Jiang, Shaoyi
      Nature Chemistry (2012), 4 (1), 59-63CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Treatment with therapeutic proteins is an attractive approach to targeting a no. of challenging diseases. Unfortunately, the native proteins themselves are often unstable in physiol. conditions, reducing bioavailability and therefore increasing the dose that is required. Conjugation with poly(ethylene glycol) (PEG) is often used to increase stability, but this has a detrimental effect on bioactivity. Here, we introduce conjugation with zwitterionic polymers such as poly(carboxybetaine). We show that poly(carboxybetaine) conjugation improves stability in a manner similar to PEGylation, but that the new conjugates retain or even improve the binding affinity as a result of enhanced protein-substrate hydrophobic interactions. This chem. opens a new avenue for the development of protein therapeutics by avoiding the need to compromise between stability and affinity.
    62. 62
      Ishihara, K. Highly lubricated polymer interfaces for advanced artificial hip joints through biomimetic design. Polymer Journal. 2015, 47 (9), 585– 597,  DOI: 10.1038/pj.2015.45
      There is no corresponding record for this reference.
    63. 63
      Cheng, G.; Xue, H.; Zhang, Z.; Chen, S.; Jiang, S. A Switchable Biocompatible Polymer Surface with Self-Sterilizing and Nonfouling Capabilities. Angewandte Chemie International Edition. 2008, 47 (46), 8831– 8834,  DOI: 10.1002/anie.200803570
      There is no corresponding record for this reference.
    64. 64
      Li, G.; Cheng, G.; Xue, H.; Chen, S.; Zhang, F.; Jiang, S. Ultra low fouling zwitterionic polymers with a biomimetic adhesive group. Biomaterials. 2008, 29 (35), 4592– 7,  DOI: 10.1016/j.biomaterials.2008.08.021
      64
      Ultra low fouling zwitterionic polymers with a biomimetic adhesive group
      Li, Guozhu; Cheng, Gang; Xue, Hong; Chen, Shengfu; Zhang, Fengbao; Jiang, Shaoyi
      Biomaterials (2008), 29 (35), 4592-4597CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Biomimetic polymers with a zwitterionic moiety for ultra low fouling and a catechol end group for surface anchoring have been developed. Binding tests of the adhesive polymers on various surfaces, including amino (NH2), hydroxyl (OH), and Me (CH3) terminated self-assembled monolayers (SAMs) along with bare gold, were performed under acidic and basic conditions. Protein adsorption from single protein solns. of fibrinogen, lysozyme, and complex media of 10-100% blood plasma and serum was measured using a surface plasmon resonance (SPR) sensor. Under optimized conditions, the coated surfaces are highly resistant to non-specific protein adsorption from both single protein solns. and blood serum/plasma. Furthermore, the 3-day accumulation of Pseudomonas aeruginosa on the coated surfaces was evaluated in situ in a laminar flow chamber. Results show that the coated surfaces are highly resistant to bacterial adhesion and biofilm formation. This work demonstrates a convenient and efficient method for using zwitterionic polymers with a catechol anchor group to achieve ultra low fouling surfaces via surface modification, for applications in complex media.
    65. 65
      Zhang, L.; Cao, Z.; Bai, T. Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat. Biotechnol. 2013, 31 (6), 553– 6,  DOI: 10.1038/nbt.2580
      65
      Zwitterionic hydrogels implanted in mice resist the foreign-body reaction
      Zhang, Lei; Cao, Zhiqiang; Bai, Tao; Carr, Louisa; Ella-Menye, Jean-Rene; Irvin, Colleen; Ratner, Buddy D.; Jiang, Shaoyi
      Nature Biotechnology (2013), 31 (6), 553-556CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      The performance of implantable biomedical devices is impeded by the foreign-body reaction, which results in formation of a dense collagenous capsule that blocks mass transport and/or elec. communication between the implant and the body. No known materials or coatings can completely prevent capsule formation. Here we demonstrate that ultra-low-fouling zwitterionic hydrogels can resist the formation of a capsule for at least 3 mo after s.c. implantation in mice. Zwitterionic hydrogels also promote angiogenesis in surrounding tissue, perhaps owing to the presence of macrophages exhibiting phenotypes assocd. with anti-inflammatory, pro-healing functions. Thus, zwitterionic hydrogels may be useful in a broad range of applications, including generation of biocompatible implantable medical devices and tissue scaffolds.
    66. 66
      Golabchi, A.; Wu, B.; Cao, B.; Bettinger, C. J.; Cui, X. T. Zwitterionic polymer/polydopamine coating reduce acute inflammatory tissue responses to neural implants. Biomaterials. 2019, 225, 119519,  DOI: 10.1016/j.biomaterials.2019.119519
      66
      Zwitterionic polymer/polydopamine coating reduce acute inflammatory tissue responses to neural implants
      Golabchi, Asiyeh; Wu, Bingchen; Cao, Bin; Bettinger, Christopher J.; Cui, Xinyan Tracy
      Biomaterials (2019), 225 (), 119519CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      The inflammatory brain tissue response to implanted neural electrode devices has hindered the longevity of these implants. Zwitterionic polymers have a potent anti-fouling effect that decreases the foreign body response to s.c. implants. In this study, we developed a nanoscale anti-fouling coating composed of zwitterionic poly (sulfobetaine methacrylate) (PSB) and polydopamine (PDA) for neural probes. The addn. of PDA improved the stability of the coating compared to PSB alone, without compromising the anti-fouling properties of the film. PDA-PSB coating reduced protein adsorption by 89% compared to bare Si samples, while fibroblast adhesion was reduced by 86%. PDA-PSB coated silicon based neural probes were implanted into mouse brain, and the inflammatory tissue responses to the implants were assessed by immunohistochem. one week after implantation. The PSB-PDA coated implants showed a significantly decreased expression of glial fibrillary acidic protein (GFAP), a marker for reactive astrocytes, within 70 μm from the electrode-tissue interface (p < 0.05). Addnl., the coating reduced the microglia activation as shown in decreased Iba-1 and lectin staining, and improved blood-brain barrier integrity indicated by reduced Ig (IgG) leakage into the tissue around the probes. These findings demonstrate that anti-fouling zwitterionic coating is effective in suppressing the acute inflammatory brain tissue response to implants, and should be further investigated for its potential to improve chronic performance of neural implants.
    67. 67
      Thorarinsdottir, H.; Kander, T.; Johansson, D.; Nilsson, B.; Klarin, B.; Sanchez, J. Blood compatibility of widely used central venous catheters; an experimental study. Sci. Rep. 2022, 12 (1), 8600,  DOI: 10.1038/s41598-022-12564-z
      There is no corresponding record for this reference.
    68. 68
      National Healthcare Safety Network (NHSN) Patient Safety Component Manual January 3rd, 2024. https://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf.
      There is no corresponding record for this reference.
    69. 69
      Lai, N. M.; Chaiyakunapruk, N.; Lai, N. A.; O’Riordan, E.; Pau, W. S.; Saint, S. Catheter impregnation, coating or bonding for reducing central venous catheter-related infections in adults. Cochrane Database Syst. Rev. 2016, 3 (3), CD007878  DOI: 10.1002/14651858.CD007878.pub3
      There is no corresponding record for this reference.
    70. 70
      Verso, M.; Agnelli, G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J. Clin Oncol. 2003, 21 (19), 3665– 75,  DOI: 10.1200/JCO.2003.08.008
      There is no corresponding record for this reference.
    71. 71
      Citla Sridhar, D.; Abou-Ismail, M. Y.; Ahuja, S. P. Central venous catheter-related thrombosis in children and adults. Thromb Res. 2020, 187, 103– 112,  DOI: 10.1016/j.thromres.2020.01.017
      71
      Central venous catheter-related thrombosis in children and adults
      Citla Sridhar, Divyaswathi; Abou-Ismail, Mouhamed Yazan; Ahuja, Sanjay P.
      Thrombosis Research (2020), 187 (), 103-112CODEN: THBRAA; ISSN:0049-3848. (Elsevier Ltd.)
      Central venous catheters (CVC) have revolutionized the care of patients requiring long-term venous access. With increasing use of CVCs, the incidence of catheter-related thrombosis (CRT) has been on the rise. CRT constitutes 10% of all deep venous thromboses (DVT) in adults and 50-80% of all DVTs among children. The incidence of CRT varies significantly based on patient characteristics, catheter-related factors and the steps involved in the process of catheter insertion. Multiple risk factors have been assocd. with a higher risk of CRT, including older age, hospitalization, CVC insertion in the subclavian vein, left-sided CVC insertion, longer duration of catheter, catheter-to-vein ratio > 0.45, and type of CVC. A majority of patients with CRT are asymptomatic. Duplex ultrasound is the initial diagnostic modality of choice, though other modalities like CT angiog. and MRV may be necessary for certain CRT locations. Current guidelines recommend maintaining a catheter unless nonfunctional or unneeded, in addn. to systemic anticoagulation. Data guiding anticoagulant management specific to upper extremity VTE is lacking, and practice is mostly extrapolated from data on lower extremities. Further studies are required to establish evidence-based guidelines in the management of adults and children with CRT, and in particular the role of direct oral anticoagulants. In this review, we describe the knowledge gaps that exist in multiple aspects of CRT and the need for large collaborative studies to improve the care of patients with CRT.
    72. 72
      Scharn, D. M.; Dirven, M.; Barendregt, W. B.; Boll, A. P.; Roelofs, D.; van der Vliet, J. A. Human umbilical vein versus heparin-bonded polyester for femoro-popliteal bypass: 5-year results of a prospective randomized multicentre trial. Eur. J. Vasc Endovasc Surg. 2008, 35 (1), 61– 7,  DOI: 10.1016/j.ejvs.2007.08.004
      There is no corresponding record for this reference.
    73. 73
      Haneya, A.; Philipp, A.; Mueller, T. Extracorporeal Circulatory Systems as a Bridge to Lung Transplantation at Remote Transplant Centers. Ann. Thorac Surg. 2011, 91 (1), 250– 255,  DOI: 10.1016/j.athoracsur.2010.09.005
      There is no corresponding record for this reference.
    74. 74
      Fischer, S.; Simon, A. R.; Welte, T. Bridge to lung transplantation with the novel pumpless interventional lung assist device NovaLung. J. Thorac Cardiovasc Surg. 2006, 131 (3), 719– 723,  DOI: 10.1016/j.jtcvs.2005.10.050
      There is no corresponding record for this reference.
    75. 75
      Strueber, M.; Hoeper, M. M.; Fischer, S. Bridge to Thoracic Organ Transplantation in Patients with Pulmonary Arterial Hypertension Using a Pumpless Lung Assist Device. Am. J. Transplant. 2009, 9 (4), 853– 857,  DOI: 10.1111/j.1600-6143.2009.02549.x
      There is no corresponding record for this reference.
    76. 76
      Camboni, D.; Philipp, A.; Arlt, M.; Pfeiffer, M.; Hilker, M.; Schmid, C. First Experience With a Paracorporeal Artificial Lung In Humans. ASAIO J. 2009, 55 (3), 304– 306,  DOI: 10.1097/MAT.0b013e31819740a0
      There is no corresponding record for this reference.
    77. 77
      Maul, T. M. ECMO Anticoagulation: It’s Still the Biggest Challenge; American Society of Artificial Internal Organs, 2015.
      There is no corresponding record for this reference.
    78. 78
      Demarest, C. T.; Shoemaker, S. J.; Chicotka, S. R. Clot Formation and Functional Changes in the CardioHelp Oxygenator Over Time. Abstract. ASAIO Journal 2016 Conference Abstracts 2016, 106
      There is no corresponding record for this reference.
    79. 79
      Hohlfelder, B.; Szumita, P. M.; Lagambina, S.; Weinhouse, G.; Degrado, JR Safety of Propofol for Oxygenator Exchange in Extracorporeal Membrane Oxygenation. ASAIO J. 2017, 63 (2), 179– 184,  DOI: 10.1097/MAT.0000000000000461
      There is no corresponding record for this reference.
    80. 80
      Philipp, A.; De Somer, F.; Foltan, M. Life span of different extracorporeal membrane systems for severe respiratory failure in the clinical practice. PLoS One. 2018, 13 (6), e0198392  DOI: 10.1371/journal.pone.0198392
      There is no corresponding record for this reference.
    81. 81
      Seeliger, B.; Dobler, M.; Friedrich, R. Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure. Crit Care. 2020, 24 (1), 701,  DOI: 10.1186/s13054-020-03348-w
      There is no corresponding record for this reference.
    82. 82
      Reser, D.; Seifert, B.; Klein, M. Retrospective analysis of outcome data with regards to the use of Phisio(R)-, Bioline(R)- or Softline(R)-coated cardiopulmonary bypass circuits in cardiac surgery. Perfusion. 2012, 27 (6), 530– 4,  DOI: 10.1177/0267659112454558
      There is no corresponding record for this reference.
    83. 83
      Sohn, N.; Marcoux, J.; Mycyk, T.; Krahn, J.; Meng, Q. The impact of different biocompatible coated cardiopulmonary bypass circuits on inflammatory response and oxidative stress. Perfusion. 2009, 24 (4), 231– 7,  DOI: 10.1177/0267659109351218
      83
      The impact of different biocompatible coated cardiopulmonary bypass circuits on inflammatory response and oxidative stress
      Sohn N; Marcoux J; Mycyk T; Krahn J; Meng Qh
      Perfusion (2009), 24 (4), 231-7 ISSN:.
      This study was to compare the impact of different biocompatible coated circuits on inflammatory response and oxidative stress induced during cardiopulmonary bypass (CPB). Seventy-eight patients undergoing elective coronary artery bypass grafting (CABG) with CPB were randomly assigned to five groups with different biocompatible coated circuits: Trillium, Bioline, Phosphorylcholine, Polymethoxyethyl acrylate (PMEA), and the uncoated control group. Blood was drawn at three different time points: before CPB, 6 and 72 hours post CPB. Unlike the Trillium group, serum levels of TNF-alpha in the Bioline and Phosphorylcholine groups significantly increased only at 72 hours post CPB (p < 0.05). Serum levels of IL-6 significantly increased at 6 and 72 hours post CPB in all groups (p < 0.01). The Trillium group showed a significant increase of IL-10 compared to the control group at 72 hours post CPB (p < 0.05). Serum levels of NOx in the Phosphorylcholine group significantly decreased at 6 hours post CPB compared to baseline (p < 0.05). Both the Bioline and Phosphorylcholine groups showed statistical decreases in serum NOx levels compared with other groups at 6 hours post CPB (p < 0.05). A significant difference in NOx levels between the Bioline and the control group was also observed at 72 hours post CPB. Myeloperoxidase levels were significantly elevated at 6 and 72 hours post CPB in all groups (p < 0.05). Inflammatory response and oxidative stress are elevated during CABG with CPB. Heparin-coated and the Phosphorylcholine-coated circuits induce less inflammatory responses and oxidative stress compared to other circuits.
    84. 84
      Marcoux, J.; Sohn, N.; McNair, E. Outcomes comparison of 5 coated cardiopulmonary bypass circuits versus an uncoated control group of patients undergoing cardiac surgery. Perfusion. 2009, 24 (5), 307– 15,  DOI: 10.1177/0267659109352114
      84
      Outcomes comparison of 5 coated cardiopulmonary bypass circuits versus an uncoated control group of patients undergoing cardiac surgery
      Marcoux J; Sohn N; McNair E; Rosin M; Smith G; Lim H; Mycyk T; Meng Q
      Perfusion (2009), 24 (5), 307-15 ISSN:.
      UNLABELLED: Attenuated inflammatory response and decreased platelet activation have been claimed repeatedly when biocompatible circuits are used for cardiopulmonary bypass. We evaluated five Health Canada approved biocompatible circuit coatings (BCC) against an un-coated control group to determine their effectiveness in improving post-operative outcomes. Patients were assigned to the Control group or one of the 5 coated circuit groups: 40 Control; 33 Trillium; 32 Phisio; 34 Bioline; 33 X; and 11 GBS. Measured outcomes included: ventilator time; ICU time; post-operative chest tube drainage and transfusion volume; high sensitivity C-reactive protein (hsCRP); tau protein; and pre- and 72-hour post-operative anti-saccadic eye movement test comparisons. RESULTS: 183 patients were enlisted into the study. One arm of the study (GBS) was abandoned after 11 patients on account of inconsistent pressure excursions within the oxygenator and the excessive consumption of platelets necessitating transfusion. Patients in the X-coated group had significantly longer ventilator and intensive care unit (ICU) time compared to the three remaining coated circuit study groups. Though not significant, patients in the X group also demonstrated the highest post-operative chest tube losses, the most platelet transfusions, the highest tau protein levels and the lowest post-operative anti-saccadic eye movement test (ASEMT) results compared to the three remaining coated groups. The patients in the Trillium, Bioline and Phisio groups showed an improvement in ventilator and ICU time relative to the Control group. The diabetic patients in the Trillium, Bioline and Phisio groups showed an improvement in bleeding relative to the diabetic patients in the Control group. CONCLUSION: We compared all 5 coated circuits approved for clinical use in Canada against an uncoated control circuit. Three of the 5 coated circuits (Trillium, Phisio and Bioline BCC) were found to improve ventilator and ICU time compared to Control. Further studies are indicated to validate these results and their impact upon approval criteria, purchasing choices and safe clinical practice, especially as applied to higher risk diabetic patients.
    85. 85
      Pieri, M.; Turla, O. G.; Calabro, M. G. A new phosphorylcholine-coated polymethylpentene oxygenator for extracorporeal membrane oxygenation: a preliminary experience. Perfusion. 2013, 28 (2), 132– 7,  DOI: 10.1177/0267659112469642
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      A new phosphorylcholine-coated polymethylpentene oxygenator for extracorporeal membrane oxygenation: a preliminary experience
      Pieri M; Turla O G; Calabro M G; Ruggeri L; Agracheva N; Zangrillo A; Pappalardo F
      Perfusion (2013), 28 (2), 132-7 ISSN:.
      Phosphorylcholine coating has a major role in the improvement of biocompatibility, durability and antihrombogenicity of the circuit for extracorporeal membrane oxygenation (ECMO). Moreover, if heparin-induced thrombocytopenia ensues, removal of all the sources of heparin is challenging if the circuit is coated with heparin. We report our preliminary experience with the new EUROSETS A.L.ONE ECMO oxygenator (Eurosets, Medolla, MO, Italy), which is aimed at providing better biocompatibility thanks to its full coating with phosphorylcholine. We retrospectively collected data on the 16 patients supported with ECMO and with the EUROSETS A.L.ONE ECMO oxygenator at San Raffaele Hospital. Mean ECMO duration was 6 ± 4 days, and 37.5% of the patients died on ECMO. Four episodes of major bleeding and three episodes of minor bleeding were recorded. The oxygenator had an excellent performance in gas exchange and the median pressure drop was 57 (26-85) mmHg at full blood flow (2.5 L/m2/min). The EUROSETS A.L.ONE ECMO oxygenator was an excellent device in our preliminary experience. Further evaluation on a larger sample is encouraged.
    86. 86
      Amoako, K.; Kaufman, R.; Haddad, W. A. M. Zwitterionic Polysulfobetaine Coating and Antiplatelet Liposomes Reduce Fouling in Artificial Lung Circuits. Macromol. Biosci. 2023, 23 (4), 2200479,  DOI: 10.1002/mabi.202200479
      There is no corresponding record for this reference.
    87. 87
      Malkin, A. D.; Ye, S. H.; Lee, E. J. Development of zwitterionic sulfobetaine block copolymer conjugation strategies for reduced platelet deposition in respiratory assist devices. J. Biomed Mater. Res. B Appl. Biomater. 2018, 106 (7), 2681– 2692,  DOI: 10.1002/jbm.b.34085
      There is no corresponding record for this reference.
    88. 88
      Ye, S. H.; Arazawa, D. T.; Zhu, Y. Hollow fiber membrane modification with functional zwitterionic macromolecules for improved thromboresistance in artificial lungs. Langmuir. 2015, 31 (8), 2463– 71,  DOI: 10.1021/la504907m
      88
      Hollow Fiber Membrane Modification with Functional Zwitterionic Macromolecules for Improved Thromboresistance in Artificial Lungs
      Ye, Sang-Ho; Arazawa, David T.; Zhu, Yang; Shankarraman, Venkat; Malkin, Alexander D.; Kimmel, Jeremy D.; Gamble, Lara J.; Ishihara, Kazuhiko; Federspiel, William J.; Wagner, William R.
      Langmuir (2015), 31 (8), 2463-2471CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Respiratory assist devices seek optimized performance in terms of gas transfer efficiency and thromboresistance to minimize device size and reduce complications assocd. with inadequate blood biocompatibility. The exchange of gas with blood occurs at the surface of the hollow fiber membranes (HFMs) used in these devices. In this study, three zwitterionic macromols. were attached to HFM surfaces to putatively improve thromboresistance: (1) carboxyl-functionalized zwitterionic phosphorylcholine (PC) and (2) sulfobetaine (SB) macromols. (mPC or mSB-COOH) prepd. by a simple thiol-ene radical polymn. and (3) a low-mol. wt. sulfobetaine (SB)-co-methacrylic acid (MA) block copolymer (SBMAb-COOH) prepd. by reversible addn.-fragmentation chain transfer (RAFT) polymn. Each macromol. type was covalently immobilized on an aminated com. HFM (Celg-A) by a condensation reaction, and HFM surface compn. changes were analyzed by XPS. Thrombotic deposition on the HFMs was investigated after contact with ovine blood in vitro. The removal of CO2 by the HFMs was also evaluated using a model respiratory assistance device. The HFMs conjugated with zwitterionic macromols. (Celg-mPC, Celg-mSB, and Celg-SBMAb) showed expected increases in phosphorus or sulfur surface content. Celg-mPC and Celg-SBMAb experienced rates of platelet deposition significantly lower than those of unmodified (Celg-A, >95% redn.) and heparin-coated (>88% redn.) control HFMs. Smaller redns. were seen with Celg-mSB. The CO2 removal rate for Celg-SBMAb HFMs remained comparable to that of Celg-A. In contrast, the rate of removal of CO2 for heparin-coated HFMs was significantly reduced. The results demonstrate a promising approach to modifying HFMs using zwitterionic macromols. for artificial lung devices with improved thromboresistance without degrdn. of gas transfer.
    89. 89
      Ye, S. H.; Orizondo, R. A.; De, B. N. Epoxy silane sulfobetaine block copolymers for simple, aqueous thromboresistant coating on ambulatory assist lung devices. J. Biomed Mater. Res. A 2024, 112 (1), 99– 109,  DOI: 10.1002/jbm.a.37619
      There is no corresponding record for this reference.
    90. 90
      Wang, Y.-B.; Shi, K.-H.; Jiang, H.-L.; Gong, Y.-K. Significantly reduced adsorption and activation of blood components in a membrane oxygenator system coated with crosslinkable zwitterionic copolymer. Acta Biomaterialia. 2016, 40, 153– 161,  DOI: 10.1016/j.actbio.2016.02.036
      There is no corresponding record for this reference.
    91. 91
      Wang, Y.-B.; Gong, M.; Yang, S.; Nakashima, K.; Gong, Y.-K. Hemocompatibility and film stability improvement of crosslinkable MPC copolymer coated polypropylene hollow fiber membrane. J. Membr. Sci. 2014, 452, 29– 36,  DOI: 10.1016/j.memsci.2013.10.032
      91
      Hemocompatibility and film stability improvement of crosslinkable 2-methacryloyloxyethyl phosphorylcholine copolymer coated polypropylene hollow fiber membrane
      Wang, Yan-Bing; Gong, Ming; Yang, Shan; Nakashima, Kenichi; Gong, Yong-Kuan
      Journal of Membrane Science (2014), 452 (), 29-36CODEN: JMESDO; ISSN:0376-7388. (Elsevier B.V.)
      Hollow fiber membranes (HFMs) based artificial lungs require a large blood-contacting membrane surface area to provide adequate gas exchange. However, such a large surface presents significant challenges to hemocompatibility. For improving the hemocompatibility, amphiphilic and cell outer membrane mimetic 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers contg. 3-(Trimethoxysilyl)propyl methacrylate (TSMA) and/or Bu methacrylate (BMA) units, poly(MPC-co-BMA-co-TSMA) (PMBT) and poly(MPC-co-BMA) (PMB) were coated on a com. polypropylene (PP) HFM. Dynamic contact angle, ATR-FTIR and XPS results showed that both the PMB and PMBT phospholipid polymer coatings are stable in water, but only the crosslinked PMBT coating can resist the dissoln. by ethanol or SDS aq. soln. Protein adsorption, platelet adhesion and whole blood contact expts. showed significant improvement in hemocompatibility after being coated with the PMBT. Moreover, oxygenation expts. indicated that the blood compatible coating could resist blood permeance and did not hinder the gas exchange. Overall these findings revealed improved hemocompatibility which can be realized through crosslinkable phospholipid polymer coating, enabling more stable and more biocompatible HFMs respiratory assist devices.
    92. 92
      Li, R.; Xu, J.; Li, Y. An endothelium membrane mimetic antithrombotic coating enables safer and longer extracorporeal membrane oxygenation application. Acta Biomater. 2024, 186, 185– 200,  DOI: 10.1016/j.actbio.2024.07.058
      There is no corresponding record for this reference.
    93. 93
      Montoya, J. P.; Shanley, C. J.; Merz, S. I.; Bartlett, R. H. Plasma leakage through microporous membranes. Role of phospholipids. ASAIO J. 1992, 38 (3), M399– 405,  DOI: 10.1097/00002480-199207000-00064
      There is no corresponding record for this reference.
    94. 94
      Ukita, R.; Ritchie, A. C.; Lai, A.; Cook, K. E. Extracorporeal Artificial Organs and Therapeutic Devices. In Biomaterials Science: An Introduction to Materials in Medicine, 4th ed.; Wagner, W. R., Sakiyama-Elbert, S. E., Guigen, E., Yaszemski, M. J., Eds.; Elsevier, 2020; Chapter 2.5.3, pp 1051– 1076.
      There is no corresponding record for this reference.
    95. 95
      Sakiyama, R.; Ishimori, I.; Akiba, T.; Mineshima, M. Effect of blood flow rate on internal filtration in a high-flux dialyzer with polysulfone membrane. J. Artif Organs. 2012, 15 (3), 266– 71,  DOI: 10.1007/s10047-012-0643-7
      There is no corresponding record for this reference.
    96. 96
      Mollahosseini, A.; Abdelrasoul, A.; Shoker, A. Latest advances in zwitterionic structures modified dialysis membranes. Materials Today Chemistry. 2020, 15, 100227,  DOI: 10.1016/j.mtchem.2019.100227
      There is no corresponding record for this reference.
    97. 97
      de Borst, M. H. The Complement System in Hemodialysis Patients: Getting to the Heart of the Matter. Nephron. 2016, 132 (1), 1– 4,  DOI: 10.1159/000443340
      There is no corresponding record for this reference.
    98. 98
      Inoshita, H.; Ohsawa, I.; Onda, K. An analysis of functional activity via the three complement pathways during hemodialysis sessions: a new insight into the association between the lectin pathway and C5 activation. Clin Kidney J. 2012, 5 (5), 401– 4,  DOI: 10.1093/ckj/sfs089
      There is no corresponding record for this reference.
    99. 99
      DeAngelis, R. A.; Reis, E. S.; Ricklin, D.; Lambris, J. D. Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis. Immunobiology. 2012, 217 (11), 1097– 105,  DOI: 10.1016/j.imbio.2012.07.012
      There is no corresponding record for this reference.
    100. 100
      Xiang, T.; Lu, T.; Xie, Y.; Zhao, W. F.; Sun, S. D.; Zhao, C. S. Zwitterionic polymer functionalization of polysulfone membrane with improved antifouling property and blood compatibility by combination of ATRP and click chemistry. Acta Biomater. 2016, 40, 162– 171,  DOI: 10.1016/j.actbio.2016.03.044
      100
      Zwitterionic polymer functionalization of polysulfone membrane with improved antifouling property and blood compatibility by combination of ATRP and click chemistry
      Xiang, Tao; Lu, Ting; Xie, Yi; Zhao, Wei-Feng; Sun, Shu-Dong; Zhao, Chang-Sheng
      Acta Biomaterialia (2016), 40 (), 162-171CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      The chem. compns. are very important for designing blood-contacting membranes with good antifouling property and blood compatibility. In this study, we propose a method combining ATRP and click chem. to introduce zwitterionic polymer of poly(sulfobetaine methacrylate) (PSBMA), neg. charged polymers of poly(sodium methacrylate) (PNaMAA) and/or poly(sodium p-styrene sulfonate) (PNaSS), to improve the antifouling property and blood compatibility of polysulfone (PSf) membranes. Attenuated total reflectance-Fourier transform IR spectra, XPS and water contact angle results confirmed the successful grafting of the functional polymers. The antifouling property and blood compatibility of the modified membranes were systematically investigated. The zwitterionic polymer (PSBMA) grafted membranes showed good resistance to protein adsorption and bacterial adhesion; the neg. charged polymer (PNaSS or PNaMAA) grafted membranes showed improved blood compatibility, esp. the anticoagulant property. Moreover, the PSBMA/PNaMAA modified membrane showed both antifouling property and anticoagulant property, and exhibited a synergistic effect in inhibiting blood coagulation. The functionalization of membrane surfaces by a combination of ATRP and click chem. is demonstrated as an effective route to improve the antifouling property and blood compatibility of membranes in blood-contact.
    101. 101
      Xie, Y.; Li, S. S.; Jiang, X.; Xiang, T.; Wang, R.; Zhao, C. S. Zwitterionic glycosyl modified polyethersulfone membranes with enhanced anti-fouling property and blood compatibility. J. Colloid Interface Sci. 2015, 443, 36– 44,  DOI: 10.1016/j.jcis.2014.11.053
      101
      Zwitterionic glycosyl modified polyethersulfone membranes with enhanced anti-fouling property and blood compatibility
      Xie, Yi; Li, Shuang-Si; Jiang, Xin; Xiang, Tao; Wang, Rui; Zhao, Chang-Sheng
      Journal of Colloid and Interface Science (2015), 443 (), 36-44CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
      Novel zwitterionic glycosyl modified polyethersulfone (PES) ultrafiltration membranes were prepd. via in-situ crosslinking polymn. coupled with phase inversion technique, and the following reactions. The membranes were characterized by FTIR spectroscopy, TGA, SEM, 1H NMR spectrum, and static water contact angles (WCAs) measurements. The modified membranes showed excellent anti-fouling property, and the flux recovery ratio could reach almost 100%. Meanwhile, the blood compatibility of the membranes was measured by protein adsorption, platelet adhesion, activated partial thromboplastin time (APTT), and thrombin time (TT). The results implied that the zwitterionic glycosyl modified PES membranes had good anti-fouling property and blood compatibility.
    102. 102
      Xiang, T.; Zhang, L. S.; Wang, R.; Xia, Y.; Su, B. H.; Zhao, C. S. Blood compatibility comparison for polysulfone membranes modified by grafting block and random zwitterionic copolymers via surface-initiated ATRP. J. Colloid Interface Sci. 2014, 432, 47– 56,  DOI: 10.1016/j.jcis.2014.06.044
      102
      Blood compatibility comparison for polysulfone membranes modified by grafting block and random zwitterionic copolymers via surface-initiated ATRP
      Xiang, Tao; Zhang, Li-Sha; Wang, Rui; Xia, Yi; Su, Bai-Hai; Zhao, Chang-Sheng
      Journal of Colloid and Interface Science (2014), 432 (), 47-56CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
      For blood-contacting materials, good blood compatibility, esp. good anticoagulant property is of great importance. Zwitterionic polymers are resistant to nonspecific protein adsorption and platelet adhesion; however, their anticoagulant property is always inadequate. Two kinds of zwitterionic copolymers (sulfobetaine methacrylate and sodium p-styrene sulfonate random copolymer and block copolymer) with sulfonic groups were covalently grafted from polysulfone (PSf) membranes via surface-initiated atom transfer radical polymn. (SI-ATRP) to improve blood compatibility. Field emission SEM (FE-SEM), attenuated total reflectance-FTIR spectra (ATR-FTIR), XPS, and static water contact angle (WCA) were applied to characterize the morphologies, chem. compns. and hydrophilicity of the modified membranes. All the zwitterionic copolymer modified membranes showed improved blood compatibility, esp. the anticoagulant property was obviously enhanced compared to the pristine PSf and simple zwitterionic polymer modified membranes. Also the random copolymer modified membranes showed better resistance to platelet adhesion than the block copolymer modified membranes. The zwitterionic copolymer modified membranes with integrated antifouling property and blood compatibility provided wide choice for specific applications such as hemodialysis, hemofiltration, and plasma sepn.
    103. 103
      Xiang, T.; Wang, R.; Zhao, W. F.; Sun, S. D.; Zhao, C. S. Covalent deposition of zwitterionic polymer and citric acid by click chemistry-enabled layer-by-layer assembly for improving the blood compatibility of polysulfone membrane. Langmuir. 2014, 30 (18), 5115– 25,  DOI: 10.1021/la5001705
      103
      Covalent Deposition of Zwitterionic Polymer and Citric Acid by Click Chemistry-Enabled Layer-by-Layer Assembly for Improving the Blood Compatibility of Polysulfone Membrane
      Xiang, Tao; Wang, Rui; Zhao, Wei-Feng; Sun, Shu-Dong; Zhao, Chang-Sheng
      Langmuir (2014), 30 (18), 5115-5125CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Development of blood compatible membranes is crit. for biomedical applications. Zwitterionic polymers have been proved to be resistant to nonspecific protein adsorption and platelet adhesion. In this work, two kinds of zwitterionic copolymers bearing alkynyl and azide groups are synthesized by atom transfer radical polymn. (ATRP) and subsequent reactions, namely alkynyl-poly(sulfobetaine methacrylate) (alkynyl-PSBMA) and azide-poly(sulfobetaine methacrylate) (azide-PSBMA). The copolymers are directly used to modify azido-functionalized polysulfone (PSf-N3) membrane via click chem.-enabled layer-by-layer (LBL) assembly. Alkynyl-citric acid is then clicked onto the membrane when the outermost layer was azide-PSBMA. The chem. compns., surface morphologies, and hydrophilicity of the zwitterionic polymer and citric acid multilayer modified membranes are characterized. The composite multilayer is resistant to protein adsorption and platelet adhesion and also prolongs clotting times, indicating that the blood compatibility is improved. Moreover, after clicking the small mol. anticoagulant alkynyl-citric acid onto the outermost of the zwitterionic multilayer, the membrane shows further improved anticoagulant property. The deposition of zwitterionic polymer and citric acid via click chem.-enabled LBL assembly can improve the blood compatibility of the PSf membrane.
    104. 104
      An, Z.; Dai, F.; Wei, C.; Zhao, Y.; Chen, L. Polydopamine/cysteine surface modified hemocompatible poly(vinylidene fluoride) hollow fiber membranes for hemodialysis. J. Biomed Mater. Res. B Appl. Biomater. 2018, 106 (8), 2869– 2877,  DOI: 10.1002/jbm.b.34106
      There is no corresponding record for this reference.
    105. 105
      Kensinger, C.; Karp, S.; Kant, R. First Implantation of Silicon Nanopore Membrane Hemofilters. ASAIO J. 2016, 62 (4), 491– 5,  DOI: 10.1097/MAT.0000000000000367
      There is no corresponding record for this reference.
    106. 106
      Kovach, K. M.; Capadona, J. R.; Gupta, A. S.; Potkay, J. A. The effects of PEG-based surface modification of PDMS microchannels on long-term hemocompatibility. J. Biomed Mater. Res. A 2014, 102 (12), 4195– 205,  DOI: 10.1002/jbm.a.35090
      There is no corresponding record for this reference.
    107. 107
      Plegue, T. J.; Kovach, K. M.; Thompson, A. J.; Potkay, J. A. Stability of Polyethylene Glycol and Zwitterionic Surface Modifications in PDMS Microfluidic Flow Chambers. Langmuir. 2018, 34 (1), 492– 502,  DOI: 10.1021/acs.langmuir.7b03095
      107
      Stability of Polyethylene Glycol and Zwitterionic Surface Modifications in PDMS Microfluidic Flow Chambers
      Plegue, Thomas J.; Kovach, Kyle M.; Thompson, Alex J.; Potkay, Joseph A.
      Langmuir (2018), 34 (1), 492-502CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Blood-material interactions are crucial to the lifetime, safety, and overall success of blood contacting devices. Hydrophilic polymer coatings have been employed to improve device lifetime by shielding blood contacting materials from the natural foreign body response, primarily the intrinsic pathway of the coagulation cascade. These coatings have the ability to repel proteins, cells, bacteria, and other microorganisms. Coatings are desired to have long-term stability, so that the nonthrombogenic and nonfouling effects gained are long lasting. Unfortunately, there exist limited studies which investigate their stability under dynamic flow conditions as encountered in a physiol. setting. In addn., direct comparisons between multiple coatings are lacking in the literature. In this study, we investigate the stability of polyethylene glycol (PEG), zwitterionic sulfobetaine silane (SBSi), and zwitterionic polyethylene glycol sulfobetaine silane (PEG-SBSi) grafted by a room temp., sequential flow chem. process on polydimethylsiloxane (PDMS) over time under ambient, static fluid (no flow), and physiol. relevant flow conditions and compare the results to uncoated PDMS controls. PEG, SBSi, and PEG-SBSi coatings maintained contact angles below 20° for up to 35 days under ambient conditions. SBSi and PEG-SBSi showed increased stability and hydrophilicity after 7 days under static conditions. They also retained contact angles ≤40° for all shear rates after 7 days under flow, demonstrating their potential for long-term stability. The effectiveness of the coatings to resist platelet adhesion was also studied under physiol. flow conditions. PEG showed a 69% redn. in adhered platelets, PEG-SBSi a significant 80% redn., and SBSi a significant 96% redn. compared to uncoated control samples, demonstrating their potential applicability for blood contacting applications. In addn., the presented coatings and their stability under shear may be of interest in other applications including marine coatings, lab. on a chip devices, and contact lenses, where it is desirable to reduce surface fouling due to proteins, cells, and other organisms.
    108. 108
      Thompson, A. J.; Ma, L. J.; Major, T. Assessing and improving the biocompatibility of microfluidic artificial lungs. Acta Biomater. 2020, 112, 190– 201,  DOI: 10.1016/j.actbio.2020.05.008
      There is no corresponding record for this reference.
    109. 109
      Dabaghi, M.; Rochow, N.; Saraei, N. A Pumpless Microfluidic Neonatal Lung Assist Device for Support of Preterm Neonates in Respiratory Distress. Adv. Sci. (Weinh). 2020, 7 (21), 2001860,  DOI: 10.1002/advs.202001860
      There is no corresponding record for this reference.
    110. 110
      Isenberg, B. C.; Vedula, E. M.; Santos, J. A Clinical-Scale Microfluidic Respiratory Assist Device with 3D Branching Vascular Networks. Adv. Sci. (Weinh). 2023, 10 (18), e2207455  DOI: 10.1002/advs.202207455
      There is no corresponding record for this reference.
    111. 111
      Roberts, T. R.; Persello, A.; Harea, G. T. First 24-h-Long Intensive Care Unit Testing of a Clinical-Scale Microfluidic Oxygenator in Swine: A Safety and Feasibility Study. ASAIO J. 2024, 70 (6), 535– 544,  DOI: 10.1097/MAT.0000000000002127
      There is no corresponding record for this reference.
    112. 112
      Iqbal, Z.; Kim, S.; Moyer, J. In vitro and in vivo hemocompatibility assessment of ultrathin sulfobetaine polymer coatings for silicon-based implants. J. Biomater Appl. 2019, 34 (2), 297– 312,  DOI: 10.1177/0885328219831044
      112
      In vitro and in vivo hemocompatibility assessment of ultrathin sulfobetaine polymer coatings for silicon-based implants
      Iqbal, Zohora; Kim, Steven; Moyer, Jarrett; Moses, Willieford; Abada, Emily; Wright, Nathan; Kim, Eun Jung; Park, Jaehyun; Fissell, William H.; Vartanian, Shant; Roy, Shuvo
      Journal of Biomaterials Applications (2019), 34 (2), 297-312CODEN: JBAPEL; ISSN:0885-3282. (Sage Publications Ltd.)
      Highly uniform silicon nanopore membranes were developed for applications in implantable bioartificial organs. A robust, readily scalable, non-fouling surface coating is required to enhance silicon nanopore membrane hemocompatibility. However, the coating must be ultrathin to keep the nanopores from occluding. Recently, zwitterionic brush polymers have demonstrated significantly lower fouling under biol. conditions. In this study, we explore ultrathin zwitterionic poly(sulfobetaine methacrylate) (pSBMA) surface coating at sub-5 nm thickness. Membrane hydraulic permeability was measured before and after surface modification of silicon nanopore membranes, and pores were found to be patent and in agreement with coating thickness measurements. Coating stability was analyzed under biol. shear as well as under blood flow in vitro and in vivo. Following exposure to shear over 24 h, coatings were characterized via XPS, goniometry, and ellipsometry, and found to survive biol. shear. In vitro blood expts. with fresh human blood as well as in vivo 7-day and 26-day implants in a porcine model demonstrate minimal platelet adhesion and activation with pSBMA surface modification compared to unmodified silicon exposed to fresh human blood in vitro. These results demonstrate that ultrathin pSBMA surface modification is a viable choice for application in blood contacting implants with crit. nanoscale features.
    113. 113
      Li, L.; Marchant, R. E.; Dubnisheva, A.; Roy, S.; Fissell, W. H. Anti-biofouling Sulfobetaine Polymer Thin Films on Silicon and Silicon Nanopore Membranes. J. Biomater Sci. Polym. Ed. 2011, 22 (1–3), 91– 106,  DOI: 10.1163/092050609X12578498982998
      113
      Anti-biofouling sulfobetaine polymer thin films on silicon and silicon nanopore membranes
      Li, Lingyan; Marchant, Roger E.; Dubnisheva, Anna; Roy, Shuvo; Fissell, William H.
      Journal of Biomaterials Science, Polymer Edition (2011), 22 (1-3), 91-106CODEN: JBSEEA; ISSN:0920-5063. (VSP)
      Silicon nanopore membranes (SNM) with monodisperse pore size distributions have potential applications in bioartificial kidneys. A protein resistant thin film coating on the SNM is required to minimize biofouling and, hence, enhance the performance efficiency of SNM. A zwitterionic polymer, poly(sulfobetaine methacrylate) (polySBMA), was used to coat silicon and SNM substrates via a surface initiated atom transfer radical polymn. method. The polySBMA-coated surfaces were characterized using contact angle goniometry, XPS, ellipsometry and SEM. Resistance of the coatings to protein fouling was examd. by measurement of fibrinogen adsorption from fibrinogen soln. and human plasma on coated silicon surfaces. Results showed that the polySBMA coating suppresses non-specific adsorption of fibrinogen. The protein-repellent property of polySBMA thin film coating is comparable to that of PEG-based coatings. Anal. of the surfaces by XPS indicated that the films remained stable when stored under physiol. conditions over a 4-wk period.
    114. 114
      Iqbal, Z.; Moses, W.; Kim, S.; Kim, E. J.; Fissell, W. H.; Roy, S. Sterilization effects on ultrathin film polymer coatings for silicon-based implantable medical devices. J. Biomed Mater. Res. B Appl. Biomater. 2018, 106 (6), 2327– 2336,  DOI: 10.1002/jbm.b.34039
      There is no corresponding record for this reference.
    115. 115
      Himmelfarb, J.; Ratner, B. Wearable artificial kidney: problems, progress and prospects. Nat. Rev. Nephrol. 2020, 16 (10), 558– 559,  DOI: 10.1038/s41581-020-0318-1
      115
      Wearable artificial kidney: problems, progress and prospects
      Himmelfarb Jonathan; Ratner Buddy
      Nature reviews. Nephrology (2020), 16 (10), 558-559 ISSN:.
      There is no expanded citation for this reference.
    116. 116
      Starling, R. C.; Moazami, N.; Silvestry, S. C. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J. Med. 2014, 370 (1), 33– 40,  DOI: 10.1056/NEJMoa1313385
      There is no corresponding record for this reference.
    117. 117
      Uriel, N.; Han, J.; Morrison, K. A. Device thrombosis in HeartMate II continuous-flow left ventricular assist devices: a multifactorial phenomenon. J. Heart Lung Transplant. 2014, 33 (1), 51– 9,  DOI: 10.1016/j.healun.2013.10.005
      There is no corresponding record for this reference.
    118. 118
      Mehra, M. R.; Goldstein, D. J.; Uriel, N. Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure. N Engl J. Med. 2018, 378 (15), 1386– 1395,  DOI: 10.1056/NEJMoa1800866
      There is no corresponding record for this reference.
    119. 119
      Kihara, S.; Yamazaki, K.; Litwak, K. N. In vivo evaluation of a MPC polymer coated continuous flow left ventricular assist system. Artif Organs. 2003, 27 (2), 188– 92,  DOI: 10.1046/j.1525-1594.2003.t01-2-06993.x
      119
      In vivo evaluation of a MPC polymer coated continuous flow left ventricular assist system
      Kihara Shin'ichiro; Yamazaki Kenji; Litwak Kenneth N; Litwak Philip; Kameneva Marina V; Ushiyama Hiroyuki; Tokuno Toshimasa; Borzelleca David C; Umezu Mitsuo; Tomioka Jun; Tagusari Osamu; Akimoto Takehide; Koyanagi Hitoshi; Kurosawa Hiromi; Kormos Robert L; Griffith Bartley P
      Artificial organs (2003), 27 (2), 188-92 ISSN:0160-564X.
      The aim of this study was the evaluation of the thrombogenicity and the biocompatibility of the SunMedical EVAHEART left ventricular assist system (LVAS) coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer compared to a diamond-like carbon (DLC) coating. Four calves were implanted with the MPC polymer-coated LVAS. Eight calves were implanted with DLC coated LVAS. The thrombogenicity and biocompatibility of the pumps were evaluated. At explant, 60.0 +/- 37.2% (5-85%) of the pump surface area was still coated with MPC polymer after the duration of 45.0 +/- 32.0 days. In 1 out of 4 MPC and 2 out of 8 DLC coated pumps, there was a very small amount of thrombus around the seal ring; otherwise the blood contacting surfaces were free of thrombus. Major organs were normal except for a few lesions in kidneys from both groups. The MPC polymer coated EVAHEART LVAS seems to have low thrombogenicity and high biocompatibility similar to the DLC coated system. The current study demonstrated that the MPC polymer coating shows great promise for being used as an antithrombogenic substrate for the LVAS due to its ease of application, significant cost benefit, and reduction in anticoagulation therapy in acute postoperative period.
    120. 120
      Snyder, T. A.; Tsukui, H.; Kihara, S. Preclinical biocompatibility assessment of the EVAHEART ventricular assist device: coating comparison and platelet activation. J. Biomed Mater. Res. A 2007, 81 (1), 85– 92,  DOI: 10.1002/jbm.a.31006
      There is no corresponding record for this reference.
    121. 121
      Ye, S. H.; Johnson, C. A., Jr; Woolley, J. R. Simple surface modification of a titanium alloy with silanated zwitterionic phosphorylcholine or sulfobetaine modifiers to reduce thrombogenicity. Colloids Surf. B Biointerfaces. 2010, 79 (2), 357– 64,  DOI: 10.1016/j.colsurfb.2010.04.018
      There is no corresponding record for this reference.