Hemocompatibility of medical connectors with biopassive or bioactive surface coatings

Although medical connectors compose very small parts of the extracorporeal circulation (ECC) system they represent a critical localization where early thromboembolic processes can manifest. In the present study we modified an in vitro closed-loop model with fresh human whole blood for the preclinical evaluation of the hemocompatibility of three types of medical connectors: non-coated (control); with silicone-, and heparin-coating. Each single loop consists of five polycarbonate connectors joined together by five pieces of silicone tubes. Thrombin-antithrombin-III, beta-thromboglobulin (beta-TG), PMN-Elastase, terminal complement complex, CD 11b expression, and surface-absorbed fibrinogen were measured. After 1 and 2 h recirculation, platelet loss, release of beta-TG, and adsorption of fibrinogen were significantly higher (p<0.05) within the non-coated connectors compared to the silicone- and heparin-coated groups. Following this experiment, the connectors were filled again with fresh heparinized whole blood from the same donor to evaluate the influence of prior blood contact. Here, the activation of platelets and coagulation was dependent on the duration of the blood preincubation period. Probably, the coated surfaces possess a reduced, or selective adsorption of plasma proteins, which in turn leads to a faster creation of a blood-friendly secondary superficial membrane, and prevents a further denaturation and hence activation of the adsorbed proteins.     

Construction and hemocompatibility study of highly bioactive heparin-functionalized surface

A simple method is developed to construct anticoagulant surfaces via passive adsorption of heparin onto the protonated plasma-polymerized allylamine (PPAam) films from phosphate-buffered saline (PBS). These protonated PPAam surfaces are found to have high affinity to heparin. Importantly, the heparin-functionalized PPAam (Hep-PPAam) surfaces show good retention of heparin after long-term immersion in PBS. The Hep-PPAam surface prolongs the activated partial thromboplastin time for about 20 s as compared to 316L stainless steel even though the adsorption amount of heparin is only about 300 ng/cm(2) . This indicates that the heparin bound to the protonated PPAam surfaces in this way maintains a high bioactivity. Blood platelet adhesion and activation on this surface is remarkably reduced and adsorption and activation of fibrinogen is inhibited. Thus, Hep-PPAam surface modification leads to a significant improve of the hemocompatibility. ? 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3124-3133, 2012.     

Oxygen and carbon dioxide transfer in membrane oxygenators

Gas transfer in membrane oxygenators can be limited by the liquid dispersion or the membrane diffusion. If limited by liquid dispersion, the increase in average oxygen saturation of blood flowing in straight gas-permeable tubes is dependent upon the flow rate, the tube length, and the diffusion coefficient and independent of the tube diameter. The mathematical solution is surprisingly insensitive to shifts of the oxyhemoglobin dissociation curve. The assumptions utilized in the model and the analytic solution were verified by a series of experiments using cattle blood. Tube staging, turbulence, and tube coiling bring about mixing and significantly improve the oxygenation rate. For coiled tubes, the oxygenation efficiency depends on the Reynolds number, the Schmidt number, and the tightness of the coil. The limit on the rate of oxygen addition and carbon dioxide removal might be imposed, for thick-walled tubes, by the diffusion through the tube wall. The wall-limited case is governed by CO₂ removal.     

Some performance aspects of porous membrane blood oxygenators

Conclusions 1. Oxygenators with porous membranes have a number of common properties that distinguish them from oxygenators with nonporous membranes, which indicates the expediency of relegating them to a special group. 2. Oxygenators with porous membranes ordinarily have higher mass transfer intensities. 3. In oxygenators with porous membranes, the appearance of gas bubbles in the liquid even with small excess liquid pressure over gas pressure, i.e., the anomalous bubbling phenomenon, is possible. 4. Anomalous bubbling is promoted by faulty initial filling of the oxygenator with liquid and by the “parasitic” pulsations that occur during roller pump operation. Scientific-Industrial Association “Kvant,” Moscow. Translated from Meditsinskaya Tekhnika, No. 4, pp. 18–22, July–August, 1990.     

Biocompatibility of standard and silica-free silicone rubber membrane oxygenators.

Spiral coil membrane oxygenators made from either standard silicone rubber or silica-free silicone rubber were compared using three priming techniques. Standard priming, carbon dioxide priming, and denucleation priming were employed with each type of device. Four-hour venovenous membrane oxygenator perfusions were carried out on awake sheep anticoagulated with heparin. Virtually no differences were observed in any parameters measured between standard silicone rubber and filler-free silicone rubber membranes. Significantly greater platelet losses occurred during the first hour of perfusion with standard priming and with carbon dioxide priming than with denucleation priming, using either type of membrane. These experiments demonstrate that denucleation priming reduces platelet losses during extracorporeal membrane oxygenator perfusion, but that the use of filler-free silicone rubber does not improve the biocompatibility of the membrane.     

Hemolytic characteristics of oxygenators during clinical extracorporeal membrane oxygenation

A connection was previously reported between the hemolytic characteristics associated with oxygenators and the pressure drop measurements in the blood chamber under experimental conditions simulating their use in cardiopulmonary bypass. We examined this association during extracorporeal membrane oxygenation (ECMO) conditions. Three oxygenators for ECMO or pediatric cardiopulmonary bypass (Menox EL4000, Dideco Module 4000, and Mera HPO-15H) were evaluated. Fresh blood from healthy Dexter strain calves anticoagulated with citrate phosphate dextrose adenine solution was used. The blood flow was fixed at 1 L/min, similar to that in ECMO. The Normalized Index of Hemolysis for Oxygenators (NIHO) has been modified according to the American Society of Testing and Materials standards, as was previously reported. The NIHO value was the lowest in the Menox (0.0070+/-0.0009) and increased from Menox to Dideco (0.0113+/-0.0099) to Mera (0.0164+/-0.0043); however, there were no significant differences among the oxygenators. This NIHO value has a close correlation to the pressure drop. In conclusion, this evaluation method is also applicable to comparison of the biocompatibility performance of different types of clinically available oxygenators for ECMO.     

Microbubble elimination during priming improves biocompatibility of membrane oxygenators

We tested the hypothesis that platelet loss following blood contact with foreign materials is partly related to the presence of microbubbles of gas (gas nuclei) trapped in surface defects on the membrane material. Extracorporeal membrane oxygenator perfusions were conducted in two groups of sheep, with use of standard priming techniques for the oxygenator in one group and a new vacuum priming technique in the other group. The vacuum priming technique was developed to eliminate gas nuclei from the oxygenator surface. With denucleation priming, platelet loss during perfusion was markedly reduced, as was thrombus formation on the membrane surface. The platelet particle-size distribution curve showed a shift consistent with platelet aggregation with the standard priming technique but not with the vacuum priming technique. We conclude that the elimination of trapped gas nuclei from the membrane surface during priming reduces the initial interaction between blood elements and the foreign surface.     

镍钛形状记忆合金表面改性后的血液相容性

背景：镍钛形状记忆合金植入人体内必需要有很好的生物相容性和生物安全性。 目的：观察分析镍钛形状记忆合金表面改性后对其生物相容性的影响。 方法：将镍钛形状记忆合金随机分为两组,经阴极电沉积法处理的材料为实验组,未经处理的为空白组,通过扫描电镜观察实验组材料表面的变化,并测定材料的溶血率和动态凝血时间。体外培养骨髓基质干细胞,与两组材料复合培养,通过MTT法检测两组材料中细胞存活数量。 结果与结论：镍钛形状记忆合金表面改性后,表面出现由很多的纳米级颗粒紧密聚集形成的Ti-O膜,实验组材料的溶血率下降,凝血时间延长,两组材料与骨髓基质干细胞复合培养第2,4,6天,实验组吸光度比空白组明显增高(P < 0.05)。说明镍钛形状记忆合金经阴极电沉积法表面改性后具有较好的生物相容性和生物安全性。     

Studies on the hemocompatibility of bacterial cellulose

Among the strategies to improve a material's hemocompatibility, pre-coating with the tripeptide Arg-Gly-Asp (RGD) is used to favor endothelialization thus lowering thrombogenicity. The blood compatibility of native and RGD-modified bacterial cellulose (BC) was studied in this work for the first time. The plasma recalcification time and whole blood clotting results demonstrate the hemocompatibility of BC. A significant amount of plasma protein adsorb to BC fibres, however, according to analysis by intrinsic tryptophan fluorescence techniques when albumin, γ-globulin, and fibrinogen from pure protein solutions adsorb to BC do not undergo detectable conformational modifications. Human microvascular endothelial cells cultured on RGD-modified BC readily form a confluent cell layer, inhibiting the adhesion of platelets. As a general conclusion, both native and RGD-modified BCs may be classified as hemocompatible materials.     

Effect of poly (2-methoxyethyl acrylate)-coated oxygenators on haemolysis

Blood contact with artificial device surfaces and mechanical trauma are two major factors for haemolysis. Poly(2-methoxyethyl acrylate) (PMEA) is an amphiphilic polymer with a polyethylene chain that is hydrophobic and a mildly hydrophilic tail. PMEA coating has showed positive effects on protein adsorption, platelet loss, platelet aggregation and post-operative bleeding in previous studies. In this study, effects of poly(2-metoxyethyl acrylate) (PMEA)-coated oxygenators on haemolysis was investigated. PMEA-coated (SX18-Capiox) oxygenators were used. Desorbed erythrocyte, free haemoglobin indirect bilirubin and total bilirubin quantities from fibre samples of oxygenators were studied. Erythrocyte, total bilirubin and direct bilirubin values were measured from blood aliquots taken in five different times during cardiopulmonary by-pass (CPB); baseline (T1), during CPB (T2), at the end of CPB (T3), after protamine injection (T4) and in intensive care (T5). In both coated and non-coated oxygenators haemolysis rate was in clinically acceptable safety range. Average desorbed free haemoglobin was 6663 mg/dl from coated and 29.405 mg/dl from non-coated fibres. Average desorbed total bilirubin was 0.0068 mg/dl from coated and 0.023 mg/dl from noncoated fibres. We observed less haemolysis, as reflected by lower desorbed free haemoglobin and indirect bilirubin from coated oxygenators and less decrease in blood erythrocyte number. Blood bilirubin concentration was low in the coated group when compared to the control group. This study describes the relationship between PMEA coating and haemolysis at the blood contacting surface. PMEA coating reduces red blood cell damage during extracorporeal circulation.     

Effect of bioactive filler content on mechanical properties and osteoconductivity of bioactive bone cement.

We took three types of bioactive bone cement (designated AWC, HAC, and TCPC), each with a different bioactive filler, and evaluated the influence of each filler on the mechanical properties and osteoconductivity of the cement. The cements consisted of bisphenol-a-glycidyl methacrylate-based (Bis-GMA based) monomers as an organic matrix, with a bioactive filler of apatite/wollastonite containing glass-ceramic (AW-GC) or sintered hydroxyapatite (HA) or beta-tricalcium phosphate (beta-TCP) powder. Each filler was mixed with the monomers in proportions of 50, 70, and 80% (w/w), giving a total of nine cement subgroups. The nine subgroups were designated AWC50, AWC70, AWC80, HAC50, HAC70, HAC80, TCPC50, TCPC70, and TCPC80. The compressive and bending strengths of AWC were found to be higher than those of HAC and TCPC for all bioactive filler contents. We also evaluated the cements in vivo by packing them into the intramedullary canals of rat tibiae. To compare the osteoconductivity of the cements, an affinity index was calculated for each cement; it equaled the length of bone in direct apposition to the cement, expressed as a percentage of the total length of the cement surface. Microradiographic examination up to 26 weeks after implantation revealed that AWC showed a higher affinity index than HAC and TCPC for each filler content although the affinity indices of all nine subgroups (especially the AWC and HAC subgroups) increased with time. New bone had formed along the AWC surface within 4 weeks, even in the cement containing AW-GC filler at only 50% (w/w); observation of the cement-bone interfaces using a scanning electron microscope showed that all the cements had directly contacted the bone. At 4 weeks the AWC had bonded to the bone via a 10 micron-thick reactive layer; the width of the layer, in which partly degraded AW-GC particles were seen, became slightly thicker with time. On the other hand, in the HAC- and TCPC-implanted tibiae, some particles on the cement surface were surrounded by new bone and partly absorbed or degraded. The results suggest that the stronger bonding between the inorganic filler and the organic matrix in the AWC cements gave them better mechanical properties. The results also indicate that the higher osteoconductivity of AWC was caused by the higher reactivity of the AW-GC powder on the cement surface.