Shoji Nagaoka

Clinical application of antithrombogenic hydrogel with long poly (ethylene oxide) chains

Thirty clinical tests on PVC drain tubes coated with hydrophilic copolymer with long poly(ethylene oxide) chains (PEO-COAT) were carried out. Controls were non-coated PVC drain tubes. Thrombogenesis was observed in 24 out of 30 non-coated PVC drain tubes (80%) and in only 4 out of 30 PEO-COAT drain tubes (13%). PEO-COAT drain tubes significantly suppressed absorption of plasma proteins and adhesion of platelets. The excellent antithrombogenic property of this hydrophilic polymer, already suggested by in vitro and in vivo experiments, was demonstrated here clinically.

Interaction Between Blood Components and Hydrogels With Poly(Oxyethylene) Chains

When a biologically imcompatible material is in contact with blood, there takes place thrombus formation on it via a rapid adsorption of plasma proteins and the subsequent adhesion of platelets. Numerous approaches to supress the adhesion of blood components onto synthetic surfaces have been studied and hydrogels are found to be useful.

Low-friction hydrophilic surface for medical devices

A hydrophilic polymer surface was developed exhibiting excellent low frictional property, namely slipperiness, when in contact with water or physiological fluid due to the reaction of epoxy-containing poly(vinyl pyrrolidone) with the polyamino compound formed on the surface of the substrate. Epoxy-containing poly(vinyl pyrrolidone) was obtained by the copolymerization of vinyl pyrrolidone as a hydrophilic component, glycidyl acrylate as a binding component to the substrate, and vinyl acetate to preserve the strength of the coating layer. The surface friction coefficient depends on the molecular weight of the coated hydrophilic copolymer. It was demonstrated that a molecular weight of 400,000 or more is essential to achieve excellent low surface friction. Using rabbit models, polyurethane catheters, both with and without the hydrophilic low friction coating, were evaluated for surface friction coefficient and blood compatibility. As a result, in the case of coated catheters, no lesions of the intima of the blood vessels and no thrombus formations on the surfaces of the catheters were observed. However, the non-coated catheters injured the intima of the blood vessels and severe thrombus formation was found on their surfaces.

Cell proliferation on hydrogels

SummaryThe adhesion and proliferation of mammalian fibroblasts (Flow 7000) on the surface of hydrophilic (copolymer ofN-vinyl-2-pyrrolidone and methyl methacrylate) and hydrophobic [polymethylmethacrylate (PMMA) stereocomplex] hydrogels with a wide range in water content were studied morphologically and quantitatively. It was demonstrated that cell proliferation on hydrogels by a static culture method decreased as the water content of the gels increased. However, it is remarkable that the cell proliferation on PMMA hydrogels with a high water content is equivalent to that on glass Petri dishes. The results obtained in the proliferation of cells on the surface of these hydrogels closely correspond to the state of cell adhesion. When fresh medium or air was perfused from the popposite side of the PMMA hydrogel membrane on which the cells were proliferating (perfusion method), the cells continued to grow into a higher density than with the conventional static culture method. In the case of fresh medium perfusion, the amount of proliferated cell was dependent on both the permeability of the membrane and the density of the membrane “scaffolding”. Virus multiplication in the cultured cells increased in proportion to the cell density, whereas the cell function was similar in both culture methods.

Low Friction Hydrophilic Surface for Medical Devices

A hydrophilic polymer surface with low friction has been devel oped. A coating can be attached by the reaction of an epoxy containing poly (vinyl pyrrolidone) with the polyamino compound formed on the surface of the substrate. The epoxy containing poly(vinyl pyrrolidone) was obtained by the copolymerization of vinyl pyrrolidone, glycidyl acrylate, and vinyl acetate. A molecular weight of 400,000 or more is essential to achieve low surface friction. Polyurethane catheters in rabbit models, both with and without the hydro philic low friction coating, were evaluated for surface friction coefficient and blood compatibility. The coated catheters produced no lesions of the intima of the blood vessels and no thrombus formation on the catheter surface, while the non-coated catheters injured the intima of the blood vessels and severe throm bus formation was found on their surfaces.

Development of Anthron®*, an Antithrombogenic Coating for Angiographic Catheters

A new heparinized hydrophilic polymer (Anthron) which contains a large amount of heparin ionically bound to the polymer matrix has been de veloped. Anthron showed excellent and long-term blood compatibility both in animal and clinical tests. It has been clarified that the long-term blood compat ibility of Anthron results from its negative membrane potential and con tinuous release of heparin from its surface into the blood at the rate of more than 0.01 unit/cm2 min. The application of Anthron for angiographic catheters was studied, and we evaluated the effects of our antithrombogenic angiographic catheter (AAC). As controls, polyurethane catheters (PUC), and polyethylene catheters (PEC), were studied in a similar manner. In addition, the mechanisms of thrombus for mation and its complications are discussed.

Evaluation of antithrombogenic thermodilution catheter

In order to prevent the complications accompanied with pulmo nary-artery (Swan-Ganz) catheterization, we have developed an antithrombo genic coating, tradenamed Anthron®.* Anthron-coated thermodilution cath eters show excellent antithrombogenicity due to continuous release of heparin from its surface to the blood stream in animal experiments. As controls, a poly (vinyl chloride) thermodilution catheter was evaluated in the similar manner. All of Anthron-coated thermodilution catheters were completely free from thrombus formation and kept excellent sensing functions for more than 3 days, while in control catheters severe thrombus formations were found both on the surfaces of the catheters and blood vessels. The sensing functions of the control catheters deteriorated with passage of time because of the deposition of the blood constituents on the thermistor.

The Activity of Immobilized Heparin via Long Poly(Ethylene Oxide) Spacers

Heparin was immobilized onto BrCN-activated Sepharose gel us ing α,ω-diaminopoly(ethylene oxide) (diamino PEO) with various chain lengths as a spacer. The heparin activity was measured on the basis of prolongation of activated partial thromboplastin time (APTT). The activity of immobilized heparin was observed after the amino groups at the terminal end of the spacer molecule, not used for immobilization of heparin, were blocked with formalde hyde. The flexible PEO spacer appeared to relieve the steric hindrance by the carrier to the formation of a heparin complex with cofactor AT III. The activity of immobilized heparin increased with elongation of the spacer chain and the highest activity was obtained when the chain length of the spacer was between 10 to 20. Longer spacer groups decreased the activity because the high mobil ity of the hydrated PEO chain hindered AT III access to the immobilized heparin.

Antithrombogenic pO2 sensor for continuous intravascular oxygen monitoring

An antithrombogenic oxygen partial pressure sensor (Anthron pO2 sensor) was produced by coating a hydrophilic heparinized polymer (Anthron) on an etched epoxy composite ultramicroelectrode (microhole electrode). From in vitro tests, both the response time and stability were satisfactory under the conditions of a 20 microns thickness of Anthron coating and a depth up to 100 microns for the microhole. Additionally, results of in vitro tests without systemic heparinization demonstrated that a stable real time measurement of the intravascular oxygen partial pressure value was possible for a long period without thrombus formation or adhesion of blood components on the electrode surface of the Anthron pO2 sensor. Moreover, the measured data agreed with those from the blood gas analyser. Due to the thick thrombus formation on the electrode surface, the control (non-coated) sensor was unable to measure the intravascular oxygen partial pressure even for a short period of time.