Improved Blood Compatibility Research Articles

Matrix engineering

Matrix engineering is a technology that utilizes hyaluronan (HA, hyaluronic acid) based matrices to control, direct or augment tissue regenerative processes. Hyaluronan and the concept of matrix engineering have become established tools in ophthalmic and orthopaedic medicine. The clinical indications for HA are limited by the physical properties and short residence time of the natural HA molecule. To expand and improve upon its current medical applications, a family of HA derivatives was prepared by chemical modification and cross-linking. Relative to the non-modified HA molecule, the hylan family of polymers provides more versatile physical forms, improved mechanical properties and an extended residence time. Hylan can also be used as a surface coating to improve blood compatibility. The chemical, physical and biological properties of hylans will be reviewed, focusing on the specific therapeutic indications they enable.

Blood compatibility of PEO grafted polyurethane and HEMA/styrene block copolymer surfaces

HEMA/styrene (HEMA/STY) block copolymers and poly(ethylene oxide) 4,000 M.W. (PEO4K) grafted Biomer (B-PEO4K) surfaces have been synthesized, characterized, and evaluated as blood-contacting materials. These surfaces have demonstrated improved blood compatibility, compared to Biomer, in in vitro and ex vivo experiments. Biomer vascular grafts (6 mm I.D. 7 cm in length) were fabricated by a dip coating process. The luminal surface was modified either with PEO grafting, HEMA/STY coating, or Biomer coating (control). These surface-modified grafts were implanted in the abdominal aortas of dogs and evaluated for graft patency and protein adsorption. Surface protein layer thickness was measured by transmission electron microscopy (TEM). B-PEO4K and Biomer showed thick multilayers of adsorbed proteins (1000-2000 A) after 3 weeks to 1 month implantation. In contrast, HEMA/STY only showed a monolayer protein thickness (less than 200 A), even after 3 months. Visualization of adsorbed plasma proteins (albumin, IgG, and fibrinogen) was performed with scanning electron microscopy (SEM)/TEM using an immunogold double antibody technique. The pattern of protein distribution showed high concentrations of fibrinogen and IgG, and less albumin adsorbed onto Biomer and B-PEO4K. In contrast, HEMA/STY showed a patchy protein distribution pattern with high concentrations of albumin and IgG, and relatively less fibrinogen. Adsorbed monolayer patterns showed improved compatibility over multilayered proteins. The Biomer and B-PEO4K grafts occluded within 1 month, while HEMA/STY grafts were patent for over 3 months. The thin and stable adsorbed protein layer on HEMA/STY surfaces may be associated with the microdomain structures of the surface, and will play an important role in long-term in vivo blood compatibility. This manuscript will evaluate the long-term in vivo performance of these polymers, analyze the extent of protein adsorption onto the surfaces, and correlate protein layer thickness to the thrombogenicity of the polymer surfaces.

Artificial Heart Valves: Improved Blood Compatibility by PECVD a‐SiC:H Coating

Implants are steadily increasing in importance as substitutions for body functions. With the present state of the art, the limitations of the application of cardiovascular implants are due to insufficient performance of biomaterials. Present research in this field is being concentrated on efforts to improve the thrombus resistance of conventional materials by coating with semiconducting materials to actively influence the electrochemical interaction between the condensed matter and blood proteins. Based on an electrochemical model of the interaction of fibrinogen with an artificial surface and the resulting requirements for improving hemocompatibility, a coating of amorphous hydrogenated silicon carbide deposited by plasma-enhanced chemical vapor deposition (PECVD) is presently under evaluation as a special coating material for cardiovascular prostheses and is herein described. In particular, first results are published concerning the optimum deposition parameters in the PECVD process and cell culture tests. Experimental results of comparative partial thromboplastin time studies serve the purpose of proving the validity of the electrochemical reaction model referring the hemocompatibility of implantable materials to their semiconducting surface properties. The aim of this article is to demonstrate a feasible method for an antithrombogenic surface modification based on doped amorphous silicon carbide films that is in full conformance to the above mentioned model.

Platelet deposition studies on copolyether urethanes modified with poly(ethylene oxide)

Pellethane ® 2363 80A films and tubings were chemically modified and the effect of these modifications on platelet deposition was studied. Grafting of high molecular weight poly(ethylene oxide) and graft polymerization of methoxy poly(ethylene glycol) 400 methacrylate resulted in surfaces with a good water wettability. The increased hydrophilicity of these modified surfaces could be demonstrated by contact angle measurements. The platelet deposition was investigated with tubings in a capillary flow system, using different types of perfusates. Platelet deposition from a buffer-containing perfusate on surfaces modified with either high molecular weight poly(ethylene oxide) or methoxy poly(ethylene glycol) 400 methacrylate was almost absent and less than on Pellethane 2363 80A. Using a citrated plasmacontaining perfusate the amount of deposited platelets on Pellethane 2363 80A modified with high molecular weight poly(ethylene oxide) was low and about the same as on unmodified surfaces. However, a marked reduced platelet deposition compared to unmodified Pellethane 2363 80A was found when the platelets were activated by Ca 2+ ionophore. The improved blood compatibility of the modified Pellethane 2363 80A tubings obviously indicates the favourable effect of the presence of grafted PEO on the surface.

Modification of natural rubber tubes for biomaterials. II. Radiation‐induced grafting of N,N‐dimethylaminoethylacrylate (DMAEA) onto natural rubber (NR) tubes

AbstractRadiation‐induced simultaneous grafting of N,N‐dimethylaminoethylacrylate (DMAEA) onto NR tubes has been studied to improve blood compatibility of NR tubes. In the grafting of DMAEA onto NR tubes, effect of grafting parameters such as solvent, monomer concentration, temperature, dose, and dose rate on the grafting yield was investigated. As the results, it was found that the grafting proceeds effectively in the presence of carbontetrachloride (CCI4) as a solvent. The initial rate of grafting was found to be proportional to 0.70 power of dose rate and to 0.95 power of monomer concentration. The activation energy for this grafting system was calculated to be 6.78 kcal/mol. The evaluation of blood compatibility of NR‐g‐DMAEA was carried out by ex vivo test. Blood compatibility of those samples was found to be dependent on only grafting yield. When the degree of grafting is higher than 30 wt %, blood compatibility of NR tube could be improved by DMAEA grafting. This is the same tendency which that of previous grafting system of NR‐g‐DMAA.

Synthesis and ESCA surface studies of octadecyl chain‐extended polyurethanes

AbstractPoly(ether urethane)s as biomaterials display certain favorable mechanical and biocompatibility properties. Earlier studies suggest that improved blood compatibility might be attained by introducing hydrocarbon groups at the surface. We synthesized and characterized a series of polyurethanes in which a N‐2,3‐dihydroxypropyl‐N′‐octadecyl urea chain extender (ODCE) was incorporated into the poly(tetramethylene glycol) (PTMO)/4,4′‐methylenebis(phenylene isocyanate) (MDI) system. Molecular weights of the polymers varied between 40,000 and 250,000. An electron spectroscopy for chemical analysis (ESCA) study of the ODCE polyurethane surface revealed a substantially enhanced hydrocarbon concentration compared to a control PTMO/MDI/ethylene diamine (ED) polyurethane surface. Also, bulk composition analyses and ESCA data of the ODCE polymers indicated that the percentage of carbon was higher in the surface region than in the bulk. Thus, the ODCE polymer showed a marked increase in hard‐segment concentration in the surface region compared to the bulk region and to the ED polymer.

Mixed Polyether-Polyester Multiblock Copolymer and its Blood Compatibility

Abstract A new type of polyether-polyester block copolymer (MPEE) consisting of two components of polyethers (PTMGT and PEGT) as soft segment and one polyester (PET) as hard segment has been synthesized. It has also been investigated in comparison with blended polyether-polyester block copolymer (BPEE) consisting of the same composition ratio of hard and soft segments and both of the two polyethers (PTMG and PEG). It was found that 1) Improvement of blood compatibility of polyether-polyester block copolymer can be achieved by introducing the hydrophilic component PEG into it; 2) generally the blood compatibility of MPEE is better than that of BPEE; 3) at a specific molar ratio of PTMGT-PET to PEGT-PET (60/40), the blended copolymer (BPEE 60/40) shows the best blood compatibility, as well as the best mechanical properties. This might be related to smaller-size microphaseseparated structures. The relationship between blood compatibility and structure of the copolymer is discussed. Polyether-polyester block ...

Surface modification for improved blood compatibility.

Several surface modification techniques are currently being used to improve the biocompatibility of blood-contacting devices. These include the immobilization of bioactive materials to prevent thrombus generation and platelet activation, the incorporation of hydrophilic grafts onto practical hydrophobic surfaces (polyurethanes) to reduce protein adsorption, and the concept of microdomain-phase separated surfaces to regulate cellular and protein adhesion.

Modification of natural rubber tubes for biomaterials I. Radiation‐induced grafting of N,N‐dimethyl acrylamide onto natural rubber tubes

AbstractRadiation‐induced simultaneous grafting of N,N‐dimethyl‐acrylamide (DMAA) onto natural rubber (NR) tubes has been studied to improve blood compatibility of the NR tubes. Concerning grafting of DMAA onto NR tubes, it was found that the grafting proceeds effectively in the presence of carbon tetrachloride (CCl4) as a solvent. The degree of grafting was found to be saturated at about 26 wt%, but a higher degree of grafting can be obtained by either “so called two‐step grafting” or “putting a standing time for a while before irradiation.” The initial grafting rate was proportional to 0.85 power of dose rate. The apparent activation energy of the graft‐copolymerization was 7.42 kcal/mol. Evaluation of blood compatibility of DMAA‐grafted NR tubes has been carried out by ex vivo test. According to the results, significant improvement of blood compatibility was obtained for the samples in which degree of grafting is higher than 30 wt%.

Plastics in medical applications.

Plastics are fulfilling a number of critical roles in a variety of medical applications. While some of these are low-technology, throw-away products, many of the applications impose critical requirements as to mechanical performance, chemical resistance, biocompatibility, ability to be sterilized and to remain sterile. By performing capably and reliably in these applications, plastics have found a major outlet, one that offers good opportunities for the present materials as well as for future developments. Numerous challenges remain. The present materials perform, though barely adequately, and superior performance over longer periods of time is an important goal. While off-the-shelf plastics have been used in most medical applications, it is likely that development work will focus on the needs of specific important medical applications. In addition to the usual need for ever decreasing costs and prices, there is the opportunity for materials that possess improved blood compatibility, radiation resistance, and/or in vivo compatibility for improved degradable sutures, coatings for pacemakers, phthalate-free plastics, bags with improved gas impermeability and disposables with controlled degradability.

Blood-Polymer Interactions at the Interface

Abstract Developing blood compatible polymeric materials and/or modifying their surfaces for improved blood compatibility is an area of interest to many researchers. However, a satisfactory small diameter vascular graft (<4 mm) still is not available. The best alternative seems to be a sephanous vein. The complex nature of the problem is based on such multiparameters [1] as surface charge, critical surface tension, surface energy and its dispersion, polar components, flow conditions, surface morphology, and chemical group distribution on the surface besides matching mechanical compliances, nontoxicity, and noninflammatory in the physiological media.

Introduction of surface functional groups onto biomaterials by glow discharges.

An attempt was made to graft the monomer HEMA to the polymer surface by "Glow discharge" technique. Experiments were carried out for different surfaces varying the exposure times of samples to HEMA and also as a function of glow discharge time. It was found that as the percentage of grafting increases the hydrophilicity also increases. Contact angle measurements were performed on these substrates, which confirmed the hydrophilic nature of the grafted samples compared to the controls. The role of protein adsorption and their effects to modulate the blood polymer interaction is briefly discussed. When a foreign material comes in contact with blood, the initial event is the adsorption of plasma proteins in parallel with the adhesion of platelets to the material. Albuminated surfaces discourage platelet adhesion while fibrinogen enhances the platelet attachment and thrombosis. Hence a decreased ratio of fibrinogen to albumin on a substrate can be correlated as an indication to its improved blood compatibility. Fibrinogen to albumin ratios of the grafted samples showed a reduction, indicating that albumin adsorption is high; which may make the modified surfaces non-thrombogenic.

A Clinical Study on Different Cellulosic Dialysis Membranes

A controlled clinical study was performed over a period of 8 weeks in two dialysis centres (Rostock, GDR, and Munich, FRG). The aim was to compare a dialysis membrane made of modified cellulose (Hemophan) with classical regenerated cellulose (Cuprophan). Dialysers containing these membranes, together with a cellulose acetate dialyser, were therefore incorporated in a cross-over programme and clinical and biochemical investigations undertaken. The efficacy of the modified cellulosic membrane with respect to urea and creatinine clearance was shown to be comparable to that of regenerated cellulose and cellulose acetate. However, modified cellulose showed an increased clearance for inorganic phosphate, significantly different from that demonstrated by both regenerated cellulose and cellulose acetate. Blood compatibility studies, which included the assessment of C3a activation and the reduction of white blood cell (WBC) and platelet count, clearly demonstrated that in comparison to regenerated cellulose, modified cellulose resulted in significantly less complement activation and WBC reduction. Similarly in comparison to cellulose acetate, modified cellulose showed reduced complement-activating and WBC-reducing properties. The reason for the improved blood compatibility of modified cellulose is not, as was originally assumed, related to binding of complement-inhibiting heparin, but appears instead to be due to the substitution of hydroxyl groups of regenerated cellulose.

Ex vivo and in vitro Blood Response to Surface-Modified Poly(styrene-b-butadiene-b-4-vinylpyridine) Triblock Polymers

An acute ex vivo canine series shunt technique, together with in vitro blood contact experiments, were used to study the blood compatibility of poly(styrene-b-butadiene-b-4-vinylpyridine) triblock polymers. The ABC type triblock polymers were solvent cast from different solvents, and were chemically modified by quaternization of the pyridine block, crosslinking of the butadiene block, and sulfonation of the styrene block. The surface properties of the polymers were studied using contact angle measurements, ESCA, ATR-IR, and SEM. The polymers cast from chloroform were more thromboresistant than those cast from a mixture of butyraldehyde and chloroform. The chloroform-cast materials were more hydrophilic and contained a greater proportion of surface nitrogen than those materials cast from the mixed solvent. Quaternization dramatically increased thrombogenicity. Subsequent crosslinking and sulfonation to produce a charge mosaic structure did not improve blood compatibility.

Polyether—urethane ionomers: surface property/ ex vivo blood compatibility relationships

The effect of incorporation of ions into polyurethanes on their interfacial interaction with blood is of interest because of the relative blood compatibility of polyurethanes, and the effect of ionic domains on surface properties and thus blood response. A series of uncharged, anionic, cationic, and zwitterionic polyetherurethanes was coated on tubing surfaces, and their blood response determined using an ex-vivo canine series shunt experiment. The results showed the polyurethane zwitterionomer and anionomer to be more thromboresistant than the uncharged polyurethane. The polyurethane cationomer was the most thrombogenic material studied. A comparison between two uncharged polyurethanes of different hard segment content showed that surface soft segment concentration correlated with thromboresistance. Multiprobe surface characterization using contact angle measurements, ESCA, ATR-IR, and SEM were used to obtain surface property information on the materials studied. The thromboresistance of the zwitterionomer and the anionomer was related to a high concentration of the mobile side chain ionic sulfonate group at the surface. Ionic mobility at the interface appears to strongly influence the blood response of these materials. Ionization of polyurethanes is thus a useful technique to both improve blood compatibility and study the role of surface chemistry in artificial surface-induced thrombosis.

Polymers with improved short term hemocompatibility obtained by radiation grafting of N-vinylpyrrolidone onto silicone rubber

NPV was grafted onto silicone tubes by the “direct” radiation method in bulk and in methanol and toluene solutions. The kinetics of the reaction were investigated at different monomer concentrations, irradiation temperatures and dose-rates of λ-rays. The penetration of the grafted front into the bulk of the silicone walls was followed by examining cross-sections of dyed tubes. It was found that in toluene solutions grafting proceeded homogeneously in the bulk. Ungrafted as well as grafted tubes were implanted into carotid arteries of 6-month old lambs for periods of 3 and 7 days. Significant improvement of blood compatibility was observed for samples having a grafting ratio in excess of 33%.

Development of blood compatible polymers using the electret effect.

AbstractExcellent in vivo thromboresistance has been obtained for FEP Teflon and for a polyether urethane prepared with electronegative surfaces using the electret effect. In vitro tissue culture studies have shown a marked improvement in tissue compatibility for negatively electrified Teflon. Studies on other materials, including Hypalon rubber, sulfonate cross‐linked Hypalon and Kel F have shown a moderate improvement in blood compatibility. These in vitro and in vivo experiments will be described. Surface physical properties of these electrified materials, including water contact angle and charge, have been measured. Correlations between surface physical measurements and blood compatibility data will be presented.

Surface microstructural factors and the blood compatibility of a silicone rubber.

AbstractAfter early failures, a series of injection molded Silastic 372 (Medical Grade) Auxiliary Ventricle surfaces became implantable, under identical hemodynamic conditions, for 3–4 weeks with no formation of adherent thrombi. Improvement in blood compatibility is attributed to a preparative technology devised to eliminate various impurities and surface inhomogeneities found by physico‐chemical and electron microscopic techniques in Silastics which thrombosed rapidly in vivo. These imperfections were traceable to processing methods and/or resulted from properties inherent to the uncured elastomer. In addition to traces of molding cavity exudates, 2,4‐dichlorobenzoic acid, a decomposition product of the Silastic's peroxide catalyst can contaminate finished elastomers in amounts varying according to curing conditions. Sodium stearate solutions used to remove impurities were found to deposit microlayers which became irreversibly adsorbed as a result of transformation into stearic acid insoluble in neutral aqueous media. Aided by the lack of strong bonding between the filler and some of the Silastic's poly‐(dimethylsiloxane), certain molding conditions can expose silica particles in submicroscopical domains inducing clots. Demonstrated by electron micrographs and transmission sections, processing technology was found to affect the submicroscopic structure which can alter the compatibility of otherwise identical Silastics within wide ranges. These factors are recognized as important determinants of compatibility.

Persistent Polarization in Polymers and Blood Compatibility

Abstract The use of persistent electrical polarization in polymers has been explored as a means of reducing surface thrombogenicity. Parallel efforts have been carried out on the characterization of surface properties related to the electret state in polymers, on the stability of the electret state in desirable prosthetic materials under simulated blood pumping conditions, and on in vitro and in vivo blood compatibility experiments. Preliminary correlations among critical surface tension, electrical polarization, and blood compatibility have been obtained. In vitro blood compatibility has been explored using both a modified Lee-White clotting test and a platelet adsorption experiment. No significant difference in clotting time was found for polarized samples; however, those with a negative charge did adsorb fewer platelets. A series of in vivo studies has been carried out using electrified right atrial flags (36) of poly-vinylidene chloride and vena cava rings (22) of FEP Teflon, Hypalon rubber, and Hypalon/2% polysulfonate. Negatively polarized samples showed improved blood compatibility in all cases. About 2/3 of the negatively charged atrial flags showed little or no thrombus and the remainder moderate thrombus whereas 2/3 of the positively charged flags showed severe thrombus. About 3/4 of the negative ring implants showed little or no thrombus. A correlation with anomalous contact angle or low charge was found in 4 of 6 cases of the rings with moderate to heavy thrombus.