Ann Thorac Surg 1999;67:1315-1319
© 1999 The Society of Thoracic Surgeons
Original Articles
Biocompatibility of a silicone-coated polypropylene hollow fiber oxygenator in an in vitro model
Hiroshi Watanabe, MDa,
Jun-ichi Hayashi, MDa,
Hajime Ohzeki, MDa,
Hisanaga Moro, MDa,
Masaaki Sugawara, MDa,
Shoji Eguchi, MDa
a Department of Thoracic and Cardiovascular Surgery, Niigata University School of Medicine, Niigata, Japan
Accepted for publication November 12, 1998.
Address reprint requests to Dr Watanabe, Department of Thoracic and Cardiovascular Surgery, Niigata University School of Medicine, 757 Asahimachi-dohri 1, Niigata City 951, Japan
e-mail: watanabe{at}med.niigata-u.ac.jp
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Abstract
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Background. A silicone-coated microporous hollow-fiber membrane oxygenator has been developed to prevent plasma leakage during long-term use. The objective of this study was to evaluate the biocompatibility of the oxygenator.
Methods. A silicone-coated oxygenator was compared with an uncoated oxygenator in an in vitro model of cardiopulmonary bypass. Simulated circulation was maintained for 6 h at 37°C.
Results. Platelet counts decreased significantly (p < 0.05) and leukocyte counts tended to decline; however, the differences between groups were not significant. Concentrations of C3a increased significantly in both groups (p < 0.05), but levels were significantly less in the silicone-coated oxygenator (p = 0.008). In contrast, concentrations of C4a, ß-thromboglobulin, and granulocyte elastase increased significantly (p < 0.05), but the differences between groups were not significant.
Conclusions. Silicone coating over a microporous hollow-fiber membrane may improve biocompatibility by reducing C3a activation.
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Introduction
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At the present time, the majority of commercially available membrane oxygenators use microporous polypropylene hollow-fiber membranes that have gas transfer advantages. Microporous membranes, however, may filter plasma across the membrane, causing a severe drop in gas transfer during long-term use [1]. This usually is not a problem during routine cardiopulmonary bypass (CPB), but it may be an issue during extracorporeal membrane oxygenation (ECMO) for respiratory assistance, where the patient may depend on the artificial lung for continuous gas exchange over days or weeks [1].
Solid films such as silicone membranes do not filter plasma through the membrane; however, the gas transfer rate of solid membranes is relatively low in comparison with microporous membranes. Silicone membrane oxygenators were abandoned after the development of microporous hydrophobic polypropylene membrane oxygenators. The wall thickness of silicone membranes was approximately 100 µm, and the low gas transfer rate was related to the thickness of the membrane. Recently, a new membrane oxygenator has been developed with a silicone-coated microporous polypropylene hollow-fiber membrane [2, 3]. The thickness of the coated silicone is approximately 0.2 µm, and the oxygenator has the same rate of gas transfer as an uncoated microporous polypropylene membrane oxygenator [2, 3]. In addition, a silicone-coated oxygenator has no possibility of plasma leakage during long-term use [3]. The silicone-coated polypropylene membrane has a nonporous surface without a blood-gas interface, and silicone has excellent blood compatibility [4]; therefore, a silicone-coated oxygenator may be more biocompatible than an uncoated oxygenator. The objective of this study was to evaluate the biocompatibility of a silicone-coated oxygenator in an in vitro model of extracorporeal circulation.
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Material and methods
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Experimental procedure
An in vitro study of simulated cardiopulmonary circulation was performed on 5 sets of two different oxygenator groups. Ten polypropylene hollow-fiber membrane oxygenators, each with a surface area of 0.8 m2, were set up with polyvinyl chloride tubes and soft reservoirs. Five sets of the oxygenators had a silicone-coated polypropylene hollow fiber (Mera Excelung Prime HPO-08H-C; Senko Medical Instrument Mfg Co, Tokyo, Japan [silicone-coated group]). The remaining sets of the oxygenators were left uncoated (Mera Excelung HPO-08H [uncoated group]) (Fig 1).
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Fig 1. Scanning electron micrographs of hollow-fiber membranes. (A) Silicone-coated membrane (original magnification, x6,220). (B) Uncoated membrane (original magnification, x5,980).
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Fresh whole human blood from informed volunteer donors was collected in bags (Terumo Corp, Tokyo, Japan), to which the anticoagulant citrate-phosphate-dextrose (CPD) had previously been added. Each set was primed with 200 mL of fresh blood and 200 mL of Ringer’s lactate. Heparin was not added to the circuit. Simulated cardiopulmonary circulation was maintained at a flow rate of 0.8 L/min for 6 h by an occlusive roller pump (Cobe Laboratories, Lakewood, CO). The blood/primer mixture was kept at 37°C with a heat exchanger. Test samples were taken immediately after hemodilution and 30, 60, 120, and 360 min after commencement of circulation. Plasma was centrifuged immediately after collection, then stored at -80°C until analysis.
Laboratory measurements
The numbers of leukocytes and platelets were determined with a cell counter (M-2000; Sysmex, Kobe, Japan). Blood concentrations of complements (C3a, C4a) were measured by a double-antibody radioimmunoassay. Blood concentrations of granulocyte elastase and ß-thromboglobulin were measured by an enzyme immunoassay. The normal ranges of blood markers are as follows: C3a, 50 to 200 ng/mL; C4a, 50 to 250 ng/mL; granulocyte elastase, 16 to 54 µg/L; ß-thromboglobulin, lower than 50 ng/mL. The measured results were corrected for hemodilution by multiplication with a derived factor (initial hematocrit/sample hematocrit).
Statistical analysis
All values are expressed as the mean ± standard error. Comparisons between the groups were assessed with repeated-measures analysis of variance (ANOVA). The Wilcoxon rank sum test was employed for comparisons of the measured values of samples taken at different periods in the same group. A p value less than 0.05 was considered statistically significant.
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Results
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Complement system
Concentrations of C3a in both groups were higher than the normal values before the start of perfusion (uncoated group, 432.2 ± 92.8 ng/mL; silicone-coated group, 445.6 ± 72.5 ng/mL). In both groups, there were significant, almost linear increases in C3a concentrations throughout the experiment (p < 0.05) (Fig 2); however, the C3a concentrations in the silicone-coated group were significantly lower than in the uncoated group (p = 0.008 by repeated measures ANOVA, oxygenator type x time effect).
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Fig 2. Plasma concentrations of C3a in cardiopulmonary circuits. Data are shown as mean plus standard error. The difference between the groups was statistically significant (p = 0.0008 by repeated measures ANOVA, oxygenator type x time effect). *p < 0.05 versus 0 min (values before the start of perfusion).
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The changes in C4a concentrations were similar to the C3a concentrations (Fig 3); however, the C4a concentrations in both groups were within the normal range before the start of perfusion (uncoated group, 125.0 ± 19.9 ng/mL; silicone-coated group, 119.0 ± 16.6 ng/mL). There was no significant difference between the groups.
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Fig 3. Plasma concentrations of C4a in cardiopulmonary circuits. Data are shown as mean plus standard error. No statistically significant difference was observed between the groups. *p < 0.05 versus 0 min (values before the start of perfusion).
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Platelet count and ß-thromboglobulin
The number of platelets was significantly reduced after 30 min in both silicone-coated and uncoated groups (p < 0.05), and there was no significant difference between the groups (Fig 4).
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Fig 4. The number of platelets in cardiopulmonary circuits. Data are shown as mean plus standard error. No statistically significant difference was observed between the groups. *p < 0.05 versus 0 min (values before the start of perfusion).
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The concentrations of ß-thromboglobulin in both groups were higher than the normal values before the start of perfusion (uncoated group, 850.4 ± 148.9 ng/mL; silicone-coated group, 723.8 ± 46.9 ng/mL). In both groups, the ß-thromboglobulin concentrations increased significantly at 30 min of perfusion (p < 0.05), (uncoated group, 2,630.0 ± 369.5 ng/mL; silicone-coated group, 2679.4 ± 186.5 ng/mL) (Fig 5). There was no significant difference between the groups.
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Fig 5. Plasma concentrations of ß-thromboglobulin in cardiopulmonary circuits. Data are shown as mean plus standard error. No statistically significant difference was observed between the groups. *p < 0.05 versus 0 min (values before the start of perfusion).
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Leukocyte count and granulocyte elastase
The number of leukocytes decreased after the start of perfusion in both groups (p < 0.05); however, there was no significant difference between the groups (Fig 6).
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Fig 6. The number of leukocytes in cardiopulmonary circuits. Data are shown as mean plus standard error. No statistically significant difference was observed between the groups. *p < 0.05 versus 0 min (values before the start of perfusion).
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The concentrations of granulocyte elastase increased significantly during the study in each group (p < 0.05); however, there were no significant differences between the groups (Fig 7).
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Fig 7. Plasma concentrations of granulocyte elastase in cardiopulmonary circuits. Data are shown as mean plus standard error. No statistically significant difference was observed between the groups. *p < 0.05 versus 0 min (values before the start of perfusion).
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Comment
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In this study, we evaluated the biocompatibility of a silicone-coated membrane oxygenator in comparison with an uncoated membrane oxygenator. Technology of silicone coating over a microporous polypropylene membrane is the same as that used in an intravascular oxygenator and carbon dioxide removal device (IVOX; Cardiopulmonics, Inc, Salt Lake City, UT) [5]. However, the wall thickness is different, ie, 0.2 µm in the Senko oxygenator and 1 µm in the IVOX [6].
Although activation of both classic and alternative pathways occurs in CPB, complement activation during CPB with a hollow-fiber membrane oxygenator takes place mainly via the alternative pathway [7]. C4 is activated via the classical pathway. In contrast, direct contact of blood and artificial surfaces directly activates C3 via the alternative pathway [8, 9]. Heparin is a well-known inhibitor of complement activation at various steps in the cascade, including at C3 in the alternative pathway [10, 11]. Because heparin was not added to the cardiopulmonary circuits in the present study, the reduction in C3 activation may be explained by the fact that the biocompatibility of silicone or no blood and gas interface suppressed activation of the alternative pathway. Because complement activation is a simple method for evaluating the biocompatibility of equipment for extracorporeal circulation [12], a silicone-coated oxygenator, in this study, was found to be more biocompatible than an uncoated one.
Platelet loss occurred in both silicone-coated and uncoated groups; there was no significant difference between the groups. There were two possible explanations for platelet loss in the silicone-coated oxygenator group: (1) that platelets were activated before the start of perfusion, suggested by the high concentration of ß-thromboglobulin at 0 min, and that activated platelets adhered to the silicone-coated surface; and (2) the fact that activated platelets adhered to the uncoated polyvinyl chloride tubes and soft reservoirs, although coated silicone reduced platelet adherence to the membrane surface. Recently, Shimono and colleagues [3] reported that a few scattered platelets adhered to the surface of silicone-coated hollow fibers after 24 h of venoarterial bypass in mongrel dogs, similar to the second possibility, mentioned above.
There are limitations of the in vitro system in the present study, which did not include a heparin-coated oxygenator. Many experimental and clinical studies have shown that heparin-coated circuits are more biocompatible than uncoated circuits [12–17]. Hence, the effect of a silicone-coated oxygenator should be compared not only with an uncoated oxygenator but also with a heparin-coated one. Because there was no comparison between silicone-coated and heparin-coated oxygenators in this study, further examinations are necessary to evaluate the biocompatibility of silicone-coated oxygenators.
This study was limited in that no uncoated tubes or reservoirs were evaluated for comparison. Although the membrane oxygenator comprises almost 90% of the total surface area in a CPB circuit, we cannot exclude the possibility that the residual surface of uncoated tubes and reservoirs provoked platelet adherence and leukocyte activation.
In conclusion, silicone coating over a microporous hollow-fiber membrane may improve biocompatibility by reducing C3a activation.
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Abstract
Introduction
