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Ann Thorac Surg 2001;71:1603-1608
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Efficacy of a new coating material, PMEA, for cardiopulmonary bypass circuits in a porcine model

^a Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
^b Research and Development, Terumo Corporation, Tokyo, Japan

Accepted for publication January 19, 2001.

Address reprint requests to Dr Sawa, Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
e-mail: sawa{at}surg1.med.osaka-u.ac.jp

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment References

 
Background. A new coating material, poly-2-methoxyethyl acrylate (PMEA), was developed to improve the biocompatibility of cardiopulmonary bypass (CPB) circuits.

Methods. To investigate the efficacy of the PMEA coating for CPB circuits, we compared PMEA-coated circuits (group P, n = 6) with uncoated circuits (group C, n = 6) and heparin (covalent-bonded heparin, Hepaface)-coated circuits (group H, n = 6) in a porcine CPB model.

Results. Platelet counts were significantly preserved in groups P and H compared with those in group C (P versus C, p < 0.05). The plasma levels of thrombin-antithrombin complex and bradykinin were significantly lower at 120 minutes in groups P and H than in group C (thrombin-antithrombin: P versus C, p < 0.05; bradykinin: P versus C, p < 0.05). The amount of fibrinogen adsorbed onto the hollow fibers was markedly less in group P than in groups C and H.

Conclusions. The PMEA coating was equal to heparin coating in preventing reactions induced by CPB circuits, and might be superior to heparin coating in suppressing the adsorption of plasma proteins such as fibrinogen. Thus, PMEA coating may be a suitable means for improving the biocompatibility of CPB circuits.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment References

 
Cardiopulmonary bypass (CPB) is well known to cause activation of inflammatory responses, resulting in the dysfunction of several organs, the so-called "postperfusion syndrome" [1–3]. During CPB, blood components are exposed to artificial surfaces, followed by the release of various inflammatory cytokines and the activation of the complement and coagulofibrinolytic systems. The heparin-coated circuit was developed to reduce systemic inflammatory reactions by lowering complement activation, decreasing neutrophil activation, and reducing plasma levels of inflammatory cytokines such as interleukin-6 and interleukin-8 [4–12]. Jansen and colleagues [13] demonstrated the advantages of heparin-coated circuits for patient recovery from the standpoint of fluid balance and postoperative intubation time. Although the heparin coating is useful for CPB circuits, its efficiency seems to have limitations in high-risk cases, such as patients with a long-term left ventricular assist system or an extracorporeal membrane oxygenator (ECMO) [14]. These patients show marked inflammatory and coagulofibrinolytic responses that often result in multiple organ failure even with heparin-coated circuits. Moreover, protamine contact with the heparin-coated surface after the implantation of the left ventricular assist system or ECMO significantly decreases the hemocompatibility of the coated surface [15].

The search for improved materials for the surfaces of artificial organs is a present focus in bioengineering [16]. Recently, we confirmed that a new coating material for artificial membranes, poly-2-methoxyethyl acrylate (PMEA), improves the biocompatibility of artificial organs [17, 18]. Therefore, we expected that PMEA would also decrease the activation of complements and the levels of several plasma proteins associated with CPB-induced inflammatory and coagulant responses. In this study, we evaluated the efficacy of PMEA-coated circuits in comparison with conventional heparin-coated and uncoated circuits in a porcine CPB model.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment References

 
Poly-2-methoxyethyl acrylate
Poly-2-methoxyethyl acrylate is an alkoxyl polymer strain. The 2-methoxyethyl acrylate monomer has been used industrially in the past [17]. We developed PMEA for use in CPB by polymerizing the monomer. Poly-2-methoxyethyl acrylate has a hydrophobic polyethylene backbone, and its residue has mild hydrophilicity with no chemical functional groups such as -OH or -NH₂. Because the outer side of the PMEA molecule is inactive chemically, we expected that once PMEA was bound, its surface would have little tendency to react with blood components. Indeed, based on our previous experience, we expected that PMEA would decrease the adsorption of several plasma proteins related to the coagulofibrinolytic system or blood platelets onto the surfaces of the oxygenator and circuit tubing, resulting in reduced activation of the blood complements [17, 18].

Percutaneous cardiopulmonary shunt circuit system
For CPB, we used a percutaneous cardiopulmonary shunt circuit system (PCPS; Capiox SX Custom Pack EBS Cardiopulmonary Set, Terumo Corp, Tokyo, Japan). The PCPS system consisted of a 1.8-m²:1.0-m² hollow fiber membrane oxygenator (Capiox SX-10), 3/8-inch polypropylene tubing, connectors, venous and arterial cannulas for pediatric use (Capiox percutaneous cannula 15F), and a centrifugal pump (CX-SP4538). All of the circuit surfaces, including the oxygenator, arterial and venous cannulas, tubes, and centrifugal pump were coated with either PMEA or the covalent-bonded heparin coating, Hepaface. Uncoated surfaces were used as the control. The PCPS system was primed with approximately 500 mL of Ringer’s solution.

Bypass procedure
Eighteen female pigs weighing approximately 20 kg each were used in the experiment. The pigs were divided into three groups: PMEA coating, group P (n = 6); heparin coating, group H (n = 6); and no coating, group C (n = 6). The pigs received a subcutaneous injection of pig anesthesia cocktail containing ketamine (100 mg), atropine (1 mg), xylazine (20 mg), and propionylpromazine (1 mL), then pentobarbiturate (150 mg) was injected through the auricular vein. Protocols were approved by the Institutional Animal Care and Use Committee, and conformed to the Guiding Principles for the Use and Care of Laboratory Animals of Osaka University Medical School. Each pig was placed in the supine position on the surgical table, intubated, and then connected to a ventilator. Anesthesia was maintained with inhalation of sevoflurane (Sevofrane, Maruishi Pharmaceutical Co, Osaka, Japan). Under mechanical ventilation (V-710, Siemens, tidal volume = 200 mL, FiO₂ = 50%), the carotid artery and the jugular vein were exposed and 15F cannulas for the PCPS system were inserted into each vessel by the cut-down method. After an intravenous 7-mL bolus of heparin sodium (350 to 400 IU/kg), CPB was established. Coagulation was activated more than 500 seconds after the administration of heparin. The perfusion flow was controlled at 1.2 L/min (60 mL · kg^-1 · min^-1), and CPB was continued for 2 hours. Bypass was performed without homologous transfusion or the use of any other blood products.

Blood samples and assays
Blood samples were taken before bypass, and at 5, 30, 60, and 120 minutes after bypass initiation. Blood gas analysis was performed at each sampling time point. In addition, at each sampling point, platelet counts were performed and thrombin-antithrombin (TAT) complex and bradykinin levels were measured. Withdrawn blood was divided into evacuated blood collection tubes (Venoject II, Terumo Co), containing either ethylenediaminetetraacetic acid (for platelet counts), Trasyrol, trypsin inhibitor, and protamine sulfate (for the bradykinin assay), or 3.8% sodium citrate (for the TAT complex assay). Platelet counts were analyzed using a Sysmex SE-9000 (Sysmex, Kobe, Japan). The platelet count at each time point was divided by the platelet count before bypass, and this ratio was recorded. Plasma samples were immediately separated by centrifugation (3,000 rpm) for 20 minutes at 4°C (Kubota 5800), then stored at -80°C until analysis. Bradykinin was measured using a radioimmunoassay kit (SRL Inc, Tokyo, Japan), and the TAT complex was measured using an enzyme immunoassay kit (SRL Inc, Tokyo, Japan). These assay procedures were followed by manufacturer’s protocols.

Adherent platelet and adsorbed protein assay
At the termination of the bypass, the PCPS system was rinsed with saline. The oxygenator was removed and treated with glutaraldehyde solution in preparation for scanning electron microscopy (SEM) (each group, n = 2). The surface of the hollow fibers of the oxygenator after bypass was then examined for adherent platelets. The oxygenator from different pigs was treated with phosphate-buffered saline, pH 7.4 for the analysis of adsorbed protein (each group, n = 3). The oxygenator was dismantled, then the hollow fibers were removed. The 300 fibers (6 cm) were put into a 15-mL plastic tube with 1% sodium dodecyl sulfate (SDS; Pharmacia Biotechnology, Sweden) and 1% Triton X-100 solution (Bio-Rad, Cambridge, MA); the tube was then placed in a 38 kHz, 80 W ultrasonic washer (Kaijyo, Tokyo, Japan) and treated for 1 hour. The sample was passed through a Millex-GV filter (Millipore, Bedford, MA), and analyzed for protein concentration by the Lowry method using a DC protein assay kit (Bio-Rad) (each group, n = 1). This eluted protein solution was stored at -80°C until analysis. For fibrinogen analysis, the eluted protein solution was combined with sample buffer containing 0.0625 mol/L Tris/HCl pH 6.8, 2% SDS, 5% 2-mercaptoethanol, 10% glycerol, and 0.002% bromophenol blue, boiled for 5 minutes, then frozen and concentrated using a vacuum drying machine. The extract of adsorbed proteins was then separated on an 8% to 16% SDS-polyacrylamide gel electrophoresis mini Gradient gel (Tefco). A 15-µL sample was put into each well. An LMW electrophoresis calibration kit (Pharmacia) was used for the molecular weight markers. The gel was electrophoretically transferred to a nitrocellulose membrane (Bio-Rad), then the membrane was blocked with Tris/HCl-buffered solution (TBS) containing 2% bovine serum albumin Fraction V (Sigma Chemical Co, St. Louis, MO) overnight. After washing the membrane with TBS solution containing 0.1% Tween 20 (Sigma) (TTBS), the membrane was incubated at room temperature for 2 hours with antipig fibrinogen diluted to 1:200 (Nordic Immunology, Netherlands). It was then washed with TTBS, and incubated with protein G gold (Bio-Rad). Fibrinogen protein was identified using a gold enhancement kit (Bio-Rad).

For groups P and C, the amount of total protein bound to fibers was also measured by the ninhydrin reaction method (each group, n = 3). In brief, fibers were combined with 6 N hydrochloric acid and heated (110°C, 24 hours). The samples were then combined with glycine, distilled water, and ninhydrin reagent (Sigma), and boiled for 15 minutes. Absorbance of the solutions was analyzed at a 570-nm wavelength using a microplate reader (iEMS Reader MF, Labsystems, Finland) (groups P and C, n = 3).

Statistical analysis
Results are expressed as the mean ± SE. One- and two-way fractional anaylses of variance were performed, as appropriate. A p value of less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment References

 
The hematocrit values during the bypass did not differ between the three groups. Blood gases were maintained with high O₂ and acceptable CO₂ throughout CPB, with no differences between the three groups (data not shown).

Platelet counts
The blood platelet counts are presented in Figure 1. In group C, the number of platelets decreased as soon as CPB was started, slightly increased at 30 minutes, and decreased again at 60 and 120 minutes. Platelet changes in groups H and P were less pronounced than in group C. In group H, at 120 minutes of CPB, the platelet count had decreased only slightly. The platelet change for group P was even less at 120 minutes of CPB. Preservation of the ratio of platelets to the prebypass level at 120 minutes of CPB was significantly better in group P than in group C (P versus C, 101.4% ± 12.6% versus 59.6% ± 5.5%, p < 0.01). There was no significant difference between the platelet counts for groups P and H at 120 minutes of CPB (P versus H, 101.4% ± 12.6% versus 86.1% ± 9.7%, p > 0.05).

View larger version (52K): [in this window] [in a new window]   Fig 1. Changes in platelet counts during cardiopulmonary bypass (CPB). The ratios of values to precounts are shown. The average values at 120 minutes of CPB were: group P, 101.4% ± 30.8%; group C, 59.56% ± 5.88%; group H, 86.1% ± 23.7%. versus C, p < 0.001. (group P = PMEA-coated circuits; group C = noncoated circuits; group H = heparin-coated circuits; PMEA = poly-2-methoxyethyl acrylate; PRE = before CPB.)

View larger version (15K): [in this window] [in a new window]   Fig 2. Changes in thrombin-antithrombin (TAT) complex levels during cardiopulmonary bypass (CPB). Suppression of the TAT complex was significant for the heparin- and PMEA-coating groups. TAT complex in the noncoated group peaked at 60 minutes of CPB. The average values at 60 minutes of CPB were: group P, 5.13 ± 2.60 pg/mL; group H, 11.5 ± 8.11 pg/mL; group C, 72.8 ± 5.88 pg/mL. versus C, p < 0.001. (group P = PMEA-coated circuits; group C = noncoated control circuits; group H = heparin-coated circuits; PMEA = poly-2-methoxyethyl acrylate; PRE = before CPB.)

View larger version (15K): [in this window] [in a new window]   Fig 3. Changes in bradykinin during cardiopulmonary bypass (CPB). Suppression of bradykinin was significant for the PMEA- and heparin-coated groups. At 120 minutes of CPB, the average values were: group P, 10.5 ± 0.48 pg/mL; group C, 42.5 ± 12.6 pg/mL; group H, 14.1 ± 2.77 pg/mL; P versus C, p < 0.005. versus C, p < 0.05. (group P = PMEA-coated circuits; group C = noncoated control circuits; group H = heparin-coated circuits; PMEA = poly-2-methoxyethyl acrylate; PRE = before CPB.)

View larger version (77K): [in this window] [in a new window]   Fig 4. Electron micrographs of the oxygenator after bypass. (A) no coating, (B) heparin coating, and (C) poly-2-methoxyethyl acrylate (PMEA) coating. Thrombus formation was observed in the no-coating group (A), but almost no adherent thrombi were observed in the PMEA- and heparin-coating groups (B, C).

The immunoblot probed with antipig fibrinogen antibodies is presented in Figure 5. Although electrophoresis was performed with the same amount of protein from each group, there were fewer bands derived from fibrinogen in group P. In group H, there were three prominent bands derived from fibrinogen that migrated at 68 kDa (band ), 55 kDa (band ß), and 47 kDa (band ). In contrast, three different prominent bands, at 44 kDa (band ß'), 42 kDa (band '), and 25 kDa (band '), were found in group C [19], indicating the cleavage of fibrinogen to fibrin by thrombin. These results demonstrate that the fibrinogen adsorbed in group C was cleaved, whereas that in group H was not.

View larger version (37K): [in this window] [in a new window]   Fig 5. Immunoblot with antipig fibrinogen of an electrophorogram of eluted protein from the oxygenators of groups with no coating, heparin coating, and poly-2-methoxyethyl acrylate (PMEA) coating. (Band , 68 kDa; ß, 55 kDa; , 47 kDa, ', 25 kDa; ß', 44 kDa, ', 42 kDa.)

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment References

Both coatings were advantageous over no coating with respect to platelet preservation, suppression of bradykinin and TAT complex, and reduction of adsorbed plasma proteins on the surface of the oxygenator hollow fibers. Although there seemed to be no significant differences in these factors between the PMEA and heparin coating, there was markedly less adsorbed fibrinogen on the PMEA-coated fibers than on the heparin-coated fibers. These data suggested that the PMEA coating might be superior to the heparin coating in anticoagulant efficiency.

Li and colleagues [20] measured changes in platelet count during CPB by analyzing platelet adhesion to the surfaces of CPB circuits treated with surface-modifying additives (SMA) using gamma scintigraphy. Their findings indicated that some circulating platelets adhered to the surface 5 to 10 minutes after the initiation of CPB, and that some of the adherent platelets might be released back into the circulation during CPB. In our study, the levels of circulating platelets were unchanged throughout CPB in group P, although we did not measure the adherent platelets during CPB. The SMA surface’s microscopic structure of alternating hydrophilic and hydrophobic regions carries a net neutral charge, thereby reducing the platelet and leukocyte deposition [20–22]. Although PMEA coating may function by a similar mechanism, differences in the changes in platelet levels between SMA and PMEA might partly result from the coating’s presence on closed versus open circuits. Surface-modifying additive is applied to the synthetic materials in the device’s production phase; therefore, its application is not a coating technique in the usual sense [15]. On the other hand, PMEA was applied to all surfaces of complete CPB systems.

The efficacy of the reduction of adsorbed platelet and plasma proteins onto the surfaces seemed to be equivalent for the PMEA- and heparin-coated circuits. However, the adsorption of fibrinogen was significantly less with the PMEA coating than with the heparin coating. Niimi and colleagues [23] reported that the adsorption of platelet adhesive proteins such as fibrinogen and von Willebrand factor was the same for heparin-coated and uncoated fibers. Our results are consistent with their report, and extend those findings. Our Western analysis of the fibrinogen that was adsorbed onto the oxygenators showed three fibrinogen bands of , ß, and in the protein extract from group H, but a different set of three bands of ', ß', and ' from group C. This result meant that the adsorbed fibrinogen detected in group H was not converted to fibrin. In contrast, in group C the adsorbed fibrinogen was converted to fibrin and was in the process of forming thrombi. The low level of fibrinogen on the PMEA-coated surface may be thrombin resistant.

Heparin coating is associated with antithrombin adsorption, and antithrombin binding to surface heparin might partly contribute to the inhibition of both platelet adhesion and the further denaturation of fibrinogen [23]. Given that little fibrinogen was adsorbed to the PMEA-coated surfaces, the mechanisms that prevent platelet aggregation must differ markedly between PMEA and heparin as coating agents. Because of the different mechanisms by which the two types of coating work, it is difficult to claim with certainty that PMEA coating is superior to heparin coating. However, CPB was continued for only 2 hours in our study, and longer CPB times might influence the adsorption of fibrinogen and other proteins, resulting in a marked difference between the two groups.

Here, we investigated a few measures relating to the contact and coagulofibrinolytic systems. However, further studies are required to more thoroughly evaluate the effectiveness of PMEA-coated circuits on the inflammatory and complement systems.

Another important factor in evaluating the potential usefulness of a coating agent is cost. Wendel and Ziemer [15] reported that the industrial heparin-coating procedure for CPB devices is costly and therefore increases their price, although few data are available on the cost efficiency of heparin-coated circuits. When PMEA coatings are developed as industrially applied materials, the coating process will be simpler and less expensive than it is for heparin coating. Therefore, PMEA may also provide a significant cost benefit when it is applied to all parts of the circuit during production.

In conclusion, PMEA as a CPB coating may be comparable or superior to heparin coating in terms of anticoagulation, biocompatibility, and cost performance.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment References

 
Hiroaki Oshiyama, Kenji Yokoyama, and Noboru Saito are employees of Terumo Cardiovascular Systems Corporation.

	References

Top Footnotes Abstract Introduction Material and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hikaru Matsuda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suhara, H. Articles by Matsuda, H. Search for Related Content PubMed PubMed Citation Articles by Suhara, H. Articles by Matsuda, H. Related Collections Cardiac - pharmacology Extracorporeal circulation