Antithrombogenic Materials Research Articles

Do antimicrobial and antithrombogenic peripherally inserted central catheter (PICC) materials prevent catheter complications? An analysis of 42,562 hospitalized medical patients.

To examine the effectiveness of antimicrobial and antithrombogenic materials incorporated into peripherally inserted central catheters (PICCs) to prevent bloodstream infection, thrombosis, and catheter occlusion. Prospective cohort study involving 52 hospitals participating in the Michigan Hospital Medicine Safety Consortium. Sample included adult hospitalized medical patients who received a PICC between January 2013 and October 2019. Coated and impregnated catheters were identified by name, brand, and device marketing or regulatory materials. Multivariable Cox proportional hazards models with robust sandwich standard error estimates accounting for the clustered nature of data were used to identify factors associated with PICC complications in coated versus noncoated devices across general care, intensive care unit (ICU), and oncology patients. Results were expressed as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Of 42,562 patients with a PICC, 39,806 (93.5%) were plain polyurethane, 2,263 (5.3%) incorporated antimicrobial materials, and 921 (2.2%) incorporated antithrombogenic materials. Most were inserted in general ward settings (n = 28,111, 66.0%), with 12, 078 (28.4%) and 1,407 (3.3%) placed in ICU and oncological settings, respectively. Within the entire cohort, 540 (1.3%) developed thrombosis, 745 (1.8%) developed bloodstream infection, and 4,090 (9.6%) developed catheter occlusion. Adjusting for known risk factors, antimicrobial PICCs were not associated with infection reduction (HR, 1.16; 95% CI, 0.82-1.64), and antithrombogenic PICCs were not associated with reduction in thrombosis and occlusion (HR, 1.15; 95% CI, 0.92-1.44). Results were consistent across populations and care settings. Antimicrobial and antithrombogenic PICCs were not associated with a reduction in major catheter complications. Guidance aimed at informing use of these devices, balancing benefits against cost, appear necessary.

Evaluation of the antithrombogenicity of poly-2-methoxyethylacrylate-coated catheters.

The blood compatibility of indwelling intravascular catheters is facilitated by the use of antithrombogenic materials. Heparin has typically been used for this purpose; however, since heparin-coated catheters are considered combination products, difficulties meeting the relevant Food and Drug Administration safety recommendations have disrupted commercialization. Other issues include coating durability and the occurrence of heparin-induced thrombocytopenia. Polymer coatings are a potential alternative; however, polymer antithrombogenicity in circulating human blood has yet to be demonstrated. The present study aimed to establish the ex vivo antithrombogenicity of a poly-2-methoxyethylacrylate (PMEA) polymer coating applied to a central venous catheter using an artificial human blood circulation system. The present study used an artificial human blood circulation system to conduct an ex vivo evaluation of the antithrombogenicity of poly-2-methoxyethylacrylate (PMEA)-coated catheters. Human blood samples obtained from volunteer donors were loaded into a circulation system fitted with either a PMEA-coated or uncoated catheter. After 3-h, the catheter was removed and examined using scanning electron microscopy. Protein adsorption on the catheter surface was investigated by shredding the catheter that had contacted the blood inside the circulation system and immersing the pieces in 1 mL of 0.5 N NaOH for 2 days. The amount of protein in the 0.5 N NaOH was determined according to the Lowry method. Adherent fibrin, which forms a sheath on the catheter surface, was observed on uncoated, but not PMEA-coated catheters. Furthermore, the amount of protein adsorption was significantly less with PMEA-coated than uncoated catheters (p = 0.043). The present findings demonstrated the antithrombogenicity of PMEA-coated catheters in circulating human blood.

Evaluating the Impact of Central Venous Catheter Materials and Design on Thrombosis: A Systematic Review and Meta-Analysis.

Thrombosis is a common complication associated with central venous catheter (CVC) insertion. Several antithrombogenic materials and alterations to catheter design have been developed to lower thrombosis rates. To systematically evaluate the effectiveness and safety of antithrombogenic materials and alterations to CVC design on thrombosis rates. A systematic search was completed of main databases (CINAHL, EMBASE, MEDLINE, and PubMed) as well as trial registries and gray literature. Randomized controlled trials conducted in any age group, published in English language since 2008 reporting impact of different CVC designs or materials on thrombosis were included, to capture studies that reflect contemporary products and practice. Cochrane systematic review methodology was followed, including independent study selection and data extraction. Quality appraisal was conducted using the Cochrane risk of bias tool. A narrative synthesis and meta-analysis in RevMan were conducted. From a possible 232 studies, nine studies met the inclusion criteria. Four studies (n=1,320) assessed different catheter materials; four studies (n=591) compared different CVC designs, and one study (n=150) evaluated impact of combined design and material on outcomes. Meta-analysis demonstrated that neither catheter material nor design alone or in combination had a significant impact on thrombosis (RR: 0.98 [95% CI 0.87, 1.11]). Different catheter materials and design also had no significant impact on occlusion or CRBSI. Studies were of mixed quality overall. Different CVC materials and designs were not associated with a reduction in the risk of either catheter-related thrombosis or infection. Overall reporting and small sample sizes make it difficult to draw firm conclusions. Larger, quality randomized trials are required to provide evidence about the possible merits of innovative catheter design and materials on patient outcomes.

A review of block copolymer‐based biomaterials that control protein and cell interactions

Block copolymers posses the ability to phase separate into micro and nanoscale patterns resulting in nonhomogeneous surfaces and solids. This nonhomogeneity has been harnessed to improve mechanical properties, control degradation, and add functionality to biomaterials. The ability of block copolymers to generate a wide variety of surface chemistries and morphologies can also be harnessed to control protein adsorption, protein conformation, and cell adhesion. Proteins and cells will respond to periodically structured surfaces, so block copolymers have a great deal of potential as biomaterials. This review will explore the ability of block copolymers to control specific biological responses such as cell adhesion, protein adsorption and conformation, parameters that govern the overall host response to a material. In addition, some of the specific applications of block copolymer, antithrombogenic materials and their ability to pattern proteins, will be discussed.

2:50 PM Abstract No. 102 - Educational Exhibit Tools of the trade: A review of biomaterials used to make guide wires and catheters, and its relevance to the interventional radiologist

Learning Objectives Review the various biomaterials used to create guide wires as well as angiographic and indwelling catheters commonly used by interventionalists 2. Compare and contrast these biomaterials across various metrics including biocompatibility, allergenicity, flexibility, radiolucency, and resistance to infection 3. Outline biomaterial considerations in the guide wire and catheter selection process. Background A wide range of biomaterials have been and are currently used to create guide wires and catheters. Each of these materials was created and/or selected based on unique characteristics designed to aid in achieving a desired effect. Biomaterials used for catheters can be divided into derivatives of three broad categories: silicones, latex rubbers, and plastic elastomer. For guide wires, composition of the inner core, outer coil, and coating must be considered. While inner and outer components of guide wires are typically composed of biologically inert metals and metallic alloys; coatings are selected from a wide range of hydrophilic, hydrophobic, and anti-thrombogenic materials. Clinical Findings/Procedure Details The benefits and disadvantages of each catheter material will be discussed. Due to the evolution of angiographic catheters which has led to the increased use of silicone derived materials in recent years, variations within the silicone derivative class will be examined. The composition materials used for guide wires remains varied. These materials will be analyzed based on goal specific performance metrics. Illustrative images will also be presented. Conclusion and/or Teaching Points The types of materials used to create guide wires and catheters is constantly evolving and expanding. A basic knowledge of the biomaterials typically used for catheters and guide wires allows the interventionalist to optimize performance of such devices.

Graft thrombosis in small diameter vascular prosthesis: A laboratory model

There are strong demands for innovative anti-thrombogenic materials, such as carbon, because of their necessity in fabricating artificial organs and progressive surgical vascular prostheses. Serial platelet deposition, surface topography, and patency were evaluated in control standard (N 45) and carbon-lined (N 45), small diameter (4 mm inner diameter) polytetrafluoroethylene grafts implanted in the abdominal aortic replacement in rabbits. A pilot study of 80 animals—40 carbon-lined (CL) and 40 standard (ST) grafts were used to develop microsurgical techniques. The 2-hour graft patency (Doppler and angiographic studies) showed better patency rate in the CL group (93% vs 80%). In 10 animals (5 ST and 5 CL grafts) the platelet deposition on each prostheses was quantitated by means of Indium 111 labeled platelets in a dual, isotope-platelet imaging technique. Platelet deposition on ST grafts 2 hours after insertion was significantly higher than on the CL grafts (6.60 ± 1.98 × 103 platelets/mm2 vs 0.82 ± 0.25 × 103 platelets/mm2; p < 0.05). Light microscopy evaluation of explanted ST midgrafts sections, including both anastomoses, indicated platelet-fibrin deposition (PFD) in nearly all prostheses, whereas only 13% of the CL grafts exhibited PFD (chi-square: 61.117; p < 0.001). Gammacamera imaging allowed scintiphotos of the grafts and cinetic acquisition. We conclude that carbon-lining decreases platelet accumulation and improves patency in small-diameter PTFE grafts in the acute phase.

Anticoagulant surface prepared by the heparinization of ionic polyurethane film

We present a new method for heparinization on the surface of polyurethane. The segmented polyurethane was first modified with an epoxide monomer and followed by a ring-opening reaction with diethanolamine to introduce sufficient hydroxyl groups on the surface of cast film. On this film surface, a cationic monomer was grafted by using tetravalent Cerium salt as an initiator. Heparin was immobilized in high efficiency on the ionized surface through static interactions in aqueous solution. The structure of ionized and heparinized surfaces were characterized by attenuated total reflectance infrared spectroscopy (ATR–FTIR) and electron spectroscopy for chemical analysis (ESCA) spectra. The platelet-rich plasma (PRP) contacting test and the platelet-poor plasma (PPP) clotting time measurements showed that the immobilized heparin retained its strong anticoagulant property. The release of heparin from film into salt solution was also studied, and it was found that only a small portion of heparin (10–20%) was released over a period as long as 10 h. It is expected that this new method for surface heparinization can be used to prepare antithrombogenic materials with long-term stability. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 76: 382–390, 2000

Peptide modified gold‐coated polyurethanes as thrombin scavenging surfaces

Thin layers of gold were deposited on polyurethane film and chemisorbed with three peptides having an N-terminal cysteine: Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and Cys-(D)Phe-Pro-Arg. The ability of these surfaces to act as thrombin scavengers was evaluated. The peptides are related to the known thrombin inhibitor Phe-Pro-Arg chloromethyl ketone and were shown to have significant thrombin inhibitory activity in solution. Attachment of the peptides to gold was confirmed by water contact angle and X-ray photoelectron spectroscopy measurements. Thrombin adsorption from a buffer and plasma was investigated, and chromogenic substrate assays were carried out for thrombin activity on the surfaces and in the supernatant following adsorption. The data suggest that the peptide-modified surfaces are able to adsorb thrombin with high affinity from a buffer and that thrombin is taken up selectively from plasma. The Cys-(D)Phe-Pro-Arg modified surfaces showed particularly high affinity for thrombin. It was also found that the activity of thrombin adsorbed on the peptide surfaces was inhibited, and inhibition was greatest on the Cys-(D)Phe-Pro-Arg surface. We concluded that the peptide surfaces may have potential as antithrombogenic materials via their ability to scavenge and inhibit thrombin generated as a result of blood–material contact. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res, 49, 66–78, 2000.

Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces.

Thin layers of gold were deposited on polyurethane film and chemisorbed with three peptides having an N-terminal cysteine: Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and Cys-(D)Phe-Pro-Arg. The ability of these surfaces to act as thrombin scavengers was evaluated. The peptides are related to the known thrombin inhibitor Phe-Pro-Arg chloromethyl ketone and were shown to have significant thrombin inhibitory activity in solution. Attachment of the peptides to gold was confirmed by water contact angle and X-ray photoelectron spectroscopy measurements. Thrombin adsorption from a buffer and plasma was investigated, and chromogenic substrate assays were carried out for thrombin activity on the surfaces and in the supernatant following adsorption. The data suggest that the peptide-modified surfaces are able to adsorb thrombin with high affinity from a buffer and that thrombin is taken up selectively from plasma. The Cys-(D)Phe-Pro-Arg modified surfaces showed particularly high affinity for thrombin. It was also found that the activity of thrombin adsorbed on the peptide surfaces was inhibited, and inhibition was greatest on the Cys-(D)Phe-Pro-Arg surface. We concluded that the peptide surfaces may have potential as antithrombogenic materials via their ability to scavenge and inhibit thrombin generated as a result of blood-material contact.

生体適合性高分子膜

Past investigations on the synthesis of biocompatible polymer materials indicate three promising ways of approach to the goal. First, antithrombogenic materials are synthesized by controlling the surface properties of the material. This approach is explained in reference to polyetherurethanes surface-grafted with polyoxyethylenes. Secondly, antithrombogenic materials are synthesized by combination of synthetic polymers with biologically active substances. This approach is explained with the examples in which heparin is bound to polyetherurethanes by ionic or covalent bondings with or without spacer chains. Thirdly, biocompatible materials are obtained by the growth of endothelial cells on the surface of the material. This approach is explained by referencing to proteinized materials seeded with endothelial cells. The third approach will be most successful in the future.

Design and Synthesis of Biocompatible Polymeric Materials

Abstract For one of the approaches to antithrombogenic materials, the combination of synthetic polymers with physiologically active substances seems to be promising. One of these ways involves crosslinked urokinase (HM-UK), in which urokinases are linked with side chains of poly(2-hydroxyethyl methacrylate) (PHEMA) by 4,4′-diisocyanatodiphenyl-methane, and encapsulated urokinase (HMe-UK), in which urokinases are encapsulated in the network of crosslinked PHEMA. The HMe-UK with a low degree of crosslinking was found to be highly antithrombogenic. For another way, Val-Pro-Arg-immobilized polyetherurethaneurea (PEUU) was synthesized. The tripeptide, Val-Pro-Arg, is a substrate of thrombin. The tripeptide-immobilized PEUU was found to complex specifically with thrombin and inactivate it, and hence to prolong the thrombin time and the active partial thromboplastin time. For a further approach to antithrombogenic materials, the design of materials which are covered with a living tissue formed by cell proliferation seems to be promising. For one of the ways in this approach, Arg-Gly-Asp-Ser-immobilized silicone films were synthesized. The tetrapeptide constitutes the active site of cell-adhesion proteins. A number of fibroblast cells were found to grow on the tetrapeptide-immobilized silicone film more resistant to changes of temperature and pH than proteins. Third, novel functions such as cell separation are expected, according to the nature of the carrier macromolecule.

Material characterization of segmented polyether poly(urethane-urea-amide)s and its implication in blood compatibility

The morphology, properties and blood compatibility of segmented polyether poly(urethane-urea-amide)s (AM series) with an aromatic diamine chain extender containing an amide group have been investigated. The AM copolymers exhibited lower moduli than the conventional segmented polyether poly(urethane-urea)s (MT series), although both series showed similar degrees of phase separation between the soft and hard segments. Electron spectroscopy for chemical analysis (e.s.c.a.) revealed that the AM copolymers had a different anisotropy of surface chemical composition for the soft and hard segments at a certain depth, compared with the MT copolymers. The relationship between e.s.c.a. measurements and platelet adhesion to the copolymer surface showed that platelet adhesion was minimized for a copolymer whose hard-segment domain had a particular surface nature. These results suggest that surface morphology, particularly the size of the hard-segment domains on the copolymer surface, has a specific effect on suppressing platelet adhesion, which could lead to the molecular design of novel antithrombogenic materials.

Recent advances in thromboresistant materials.

There are strong demands for innovative antithrombogenic materials, because of their necessity in fabricating artificial organs and progressive surgical prostheses. This paper reviews the recent advances in thromboresistant materials. Special emphasis is placed on the novel feature of the surface characterization of thromboresistant materials by X-ray photoelectron spectroscopy and its biomedical implications. Essential role of crystalline-amorphous microstructured surface in thromboresistant property of semicrystalline segmented copolymer is also discussed in detail.

ESCA study of new antithrombogenic materials: Surface composition of poly(propylene oxide)‐segmented nylon 610 and its blood compatibility

AbstractSurface composition and blood compatibility of a series of segmented polymers based on poly(propylene oxide) (PPO) and nylon 610 were investigated. Electron spectroscopy for chemical analysis (ESCA) measurements revealed that the chemical composition of PPO‐segmented nylon 610 surface is regulated by nylon 610 crystallization, and the PPO enrichment effect on the air‐facing surface was correlated with both the degree of crystallinity of nylon 610 and the nylon 610 crystallite thickness. Platelet adhesion was minimized for the copolymer having a long period of approximately 12 nm and a crystallite thickness of 6,5 nm. This copolymer surface had the same chemical composition as the bulk, indicating that the particular surface microstructure composed of crystalline and amorphous phases could be a determining factor for suppressing platelet adhesion.

血液適合性材料の分子設計

There are strong demands for innovative antithrombogenic materials in the field of clinical medicine, because of their necessity in fabricating implantable artificial organs and progressive surgical prosthesis. This paper reviews the present status of the development of antithrombogenic materials. Special emphasis was placed on the promising feature of microdomain structured polymers as antithrombogenic materials. A series of studies reviewed in this paper demonstrates that contact-induced activation of blood platelets, a triggering phenomenon of thrombosis, could be eliminated by designing a polymer surface to have appropriate microdomain structure. As a possible mechanism involved in this suppressive effect on activation of platelets, we have proposed a mechanism of “capping control”. In this proposed mechanism, we emphasize the close relationship between reorganization of cytoskeletal components and assemblage of membrane glycoproteins at polymer/platelet interface.

Physical theory of some interface phenomena in hemorheology.

The following four subjects are discussed theoretically from a physical standpoint: (1) the effect of the wall of a capillary viscometer on the apparent viscosity of blood; (2) the effect of electric charge on capillary flow; (3) the electric aspect of platelet adhesion and aggregation; and (4) multiphase polymeric materials as antithrombogenic materials. Copley and Scott Blair found a remarkable decrease in the apparent viscosities of blood, plasma, and serum in a fibrin-coated glass tube as compared with those in a glass tube without fibrin-coating. It is shown that the phenomenon cannot be explained by the existence of an electric double layer unless the zeta potential is positive. It is suggested that a reduction of the apparent viscosity of blood may be explained by a slight increase in the thickness of a plasma layer. It is shown that the existence of a slight gap between red cells and the capillary wall due to an electrostatic repulsion will remarkably lower the capillary flow resistance. An electric aspect of endothelial injury is discussed in relation to the adhesion of platelets to the injured endothelium. Platelet aggregation is discussed in accordance with the theory of Verwey and Overbeek , and a possible mechanism of thrombus formation due to a turbulent motion of blood is suggested. The significance of a multiphase polymeric material for an antithrombogenic surface is emphasized. It is suggested that sufficiently large conformational change of macromolecules will be favorable to antithrombogenicity of a polymeric material.

Studies on antithrombogenicity of immobilized urokinase

Urokinase (UK), a plasminogen activator was immobilized on nylon and silicone surface by application of a newly devised technique.The antithrombogenicity of these materials was studied in vitro and UK-immobilized nylon tubes were applied clinically, which proved to be available as antithrombogenic material.Methods: In our newly devised technique of immobilization of UK, nitrophthalic anhydride (NP) was used as an anti-urokinase inhibitor, polyethylene imine (PEI) and Gantrez (G), a copolymer of maleic anhydride and methyl vinyl ether were used to increase the quantity of UK immobilized on carrier. The nylon tubes immobilized UK in this technique were shown as “nyl-G·NP-UK” and the silicone tubes, as “sil-G·NP-UK”. Details of the immobilization procedures are shown Fig. 1.The antithrombogenicity of these materials was investigated in vitro, in two different ways: one was lysis areas by standard fibrin plate method and the other was thrombus formation time (TFT) according to the method of Chandler. In the latter studies, a comparison was made with non-treated nylon and silicone tubes, NP-immobilized nylon tubes, G-immobilized nylon tubes and casein-immobilized nylon tubes.UK-immobilized nylon tubes, 2mm in outer diameter, 1.7mm in internal diameter were applied to surgical drains in 28 patients who had undergone thyroid, breast and thoracic surgery. Three of these were served as IVH tubes. All these tubes had been disinfected using ethylene oxide gas (EOG) before the clinical use.Silicone tubes, 3mm in outer diameter, 2mm in internal diameter were used as control materials. Fibrinolytic activity was also tested before and after the clinical application of the materials by the standard fibrin plate method.Results: Thrombus formation time of nyl-G·NP-UK was over 45 minutes.That of sil-G·NP-UK was various, however, longer than that of other materials. These results are illustrated in Fig. 2.When the UK-immobilized tubes were clinically applied as drains, blood coagula did not form in the lumina of the tubes for the duration of the clinical application, while in the case of silicone tubes, blood coagula obstructed the lumina within 12-48 hours. The patency of these tubes are summarized in Table 1.Even after termination of clinical application, the UK-immobilized tubes maintained the plasminogen activating activities.Discussion: The UK-immobilized nylon tubes showed excellent thromboresistance, both in vitro and in vivo, and such is attributed to the specificity of the surface of the material covered with UK and NP. Silicone is one of the most widely applied clinical materials, however, the degree of antithrombogenicity revealed to be unsatisfactory (Fig. 2).Antithrombogenicity regarding the UK-immobilized silicone tubes are to be investigated.In our clinical studies, the drainage with our newly devised tubes was excellent and the patency of the tubes was also satisfactory.The UK-immobilized nylon tubes show a great promise for application as antithrombogenic materials.

The mechnical behaviors on nonthrombogenecity

Synthetic polymers suitable for use in the cardiovascular system are needed as biomaterials for heart valve prostheses, artificial heart, veins, arteries and extracorporeal circulatory devices as heart-lung and kidney machines. Despite the wide variety of synthetic polymers that are available in the form of plastics or elastomers, none has proven eligible to clinical application for this purpose as a perfectly nonthrombogenic material. Currently, most investigations seem to be directed toward clarification of the blood biomaterial surface interaction, especially the mechanism whereby thrombi are formed in contact with such prosthetic. In many of these studies the surface properties of synthetic materials are being investigated from the angle where the foreign surface: blood interaction is taken as interface reaction, with the attention focused upon hydrophobicity, hydrophilicity and electronegativity of the materials. Findings obtained in our studies aimed at development of antithrombogenic materials have indicated importance of a definite distribution density of hydrophobicity and hydrophilicity for such polymers; namely, it appears unlikely that no surface factor is involved in the biomaterial: blood interface.Supposing, for example, that a synthetic venous prosthesis with a surface of about 15cm2 be introduced into the vascular system, this newly added surface of about 15cm2 undoubtedly would be so slight as to fall within the limits of errors as compared with the entire inner surface of the cardiovascular system and hence as viewed in terms of the concentration of heparin injected for inhibition of the clotting system. Thus it would be rational to introduce into the study the findings on the surface structure of cells exposed to the cardiovacular lumen. Our studies are based on this ground, pursued through physico-chemical analysis of the interface comprised of the prosthetic surface and the circulating plasma surface. By comparative evaluation of various synthetic polymer prostheses in terms of antithrombogencity, the interfacial condition of the vascular inner surface of the organism was determind to consist of γC(Zis.)=20 to 30erg/cm2, γC=68.5erg/cm2 and γSL(H2O)=0erg/cm2, or the surface endowed both with hydrophilicity and it was demonstrated that a synthetic polymer fulfilling the prerequisites of γC(Zis.)=29 to 30erg/cm2, γC=29 to 30erg/cm2 and γSL(H2O)=0erg/cm2 is remarkably antithrombogenic. The results, stress prime importance of the function of interface to protein at a synthetic polymer surface and indicate the presence of biomate rials with minimal bearing upon the clotting system of blood. Further studies aimed at clarification of the interaction with protein will be pursued, using such materials.

Role of surface micro-heterogeneous structure in antithrombogenic materials

Role of surface micro-heterogeneous structure in antithrombogenic materials

Studies on antithrombogenic materials and agents

Studies on antithrombogenic materials and agents