J . BIOJIEl). JIATEH. RES. VOL. 4, PP. 25-28 (1970)

The Effect of n-Butyl 2-Cyanoacrylate on Liver Function

STUART HOUSTON, DOUGLAS I(. OUSTERHOUT, KENNETH H. SLEEMAN, and FRED I,EONARD, U.X. Army Medical Bio- mechanical Research Laboratory, Walter Reed Army Medical Center,

Washington, D.C. 20012

Summary n-Butyl 2-cyanoacrylate was implanted subcutaneously in dogs and eight

different liver function tests were employed over a 6-month period in order to determine the effect of the cyanoacrylate on liver function. The biochemical results indicated that all the values obtained were within the normal range of values reported for the dog. Pathological studies on all vital organs showed that the subcutaneously implanted cyanoacrylate polymer did not appear to cause harmful effects on the vital organs.

INTRODUCTION

The alkyl 2-cyanoacrylate rapidly polymerizing monomers have been evaluated extensively in animals and, to a limited degree, clinically as hemostatic agents and tissue adhesives in nonsuture closure of wounds, or as adjuncts to surgical sutures.

The polymers have been found to be biodegradable and it has been reported that methyl 2-cyanoacrylate degrades in vivo at a rate of approximately 0.6% day,' while the in vivo degradation rate of n-butyl 2-cyanoacrylate is approximately 0.03% day.2 However, because the methyl homolog is locally very tissue toxic, possibly due to the rela- tively high concentration of degradation products at the implant site, the less histotoxic higher homologs are presently receiving more attention. It has been shown that in vitro, the degradation products of alkyl 2-cyanoacrylate may include formaldehyde and an alkyl ~yanoacetate.~ Reynolds et al.* applied methyl 2-cyanoacrylate-2- I4C in rat skin incisions and subsequently demonstrated an initial

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@ 1970 by John Wiley & Sonh, Inc.

26 HOUSTON ET AL.

radioactivity in the liver and other organs. The radioactivity then decreased with time, up to 24 days, at which time it was slightly in excess of the controls.

Since radioactivity from the degradation of methyl 2-cyano- a~rylate-2-'~C has been demonstrated in the rat liver, it became of interest t o determine what effect subcutaneous implantation of 2- cyanoacrylates might have on liver function. The results of this investigation are herein reported.

MATERIALS AND METHOD

Sixteen one-year-old beagle dogs were randomly divided into two equal-sized control and experimental groups. The animals were fed dry food and were housed in a covered outdoor enclosure during the period of the study.

The following liver function studies were made on all 16 animals: Serum glutamic-oxalacetic transaminase, serum glutamic-pyruvic transaminase, lactic dehydrogenase, isocitric dehydrogenase, pro- thrombin time, partial thromboplastin time, sulfobromophthalein uptake, and bilirubin. The kit method for measurement of SGOT, SGPT, LDH, and ICDH was employed. The technique for deter- mination of prothrombin time and partial thromboplastin time was that described by Ei~helberger.~ The technique of Gradwoh16 was followed in the determination of BSP, and RIallory and Evelyn' method was used in determination of bilirubin values.

Blood samples were obtained at 10 different dates prior to implanta- tion of the cyanoacrylate in order to obtain a normal base line. After these values were obtained, half of the animals were injected subcuta- neously with n-butyl 2-cyanoacrylate a t a dosage of 400 mg per kilogram body weight. Blood samples were then drawn at the following intervals: 1 , 3 , 7 , and 14 days, and each month for 6 months. All animals were necropsied and histologic studies made of the vital organs a t the end of the 6-month period.

RESULTS

The results of the various enzymatic, biochemical and clotting determinations are summarized in Table I. While a comparison of the means of each test before and after cyanoacrylate implantation ( t test) revealed a statistically significant decrease in LDH, ICDH,

n-BUTYL 2-CYANOACRYLATE 27

TABLE I Tabulated Results of Liver Function Tests

_.

Normal Pre-injection Poseinjection

Test for the dog (Mean f SE) (Mean f SE)

SGPT 22-30 23.4 f 1.78 28.2 f 2.73 PTTb 14-25.7 16.7 f 0.34 18.1 f 0.32 PTb 6-9 7.7 f 0.19 7 .2 f 0.20 BSP <5% 2.5 f 0.26 2 . 1 f 0.20 Bilirubind .I-1 0.39 f 0.04 0.26 f 0.01 ICDHa 80-200 178.0 f 15.78 157.6 f 11.32 SGOT * 28 28.4 f 2.06 27.9 f 1.62 LDH 8 140-455 404.2 f 15.37 222.3 f 15.80

range control control

a Sigma units. b Seconds. c yo, Retention.

mg/100 ml.

and bilirubin, and a statistically significant increase in PTT and SGPT, the results from all studies were within the reported normal range values for these tests.

Gross and histologic studies indicated that the cyanoacrylate had no untoward effect on the vital organs. Of the animals examined, one had a small adrenal cortical adenoma and another, adenomatous hyperplasia of the prostate gland. We feel that both of these findings were incidental and were unrelated to the presence of the cyano- acrylate polymer.

DISCUSSION

Liver function did not appear to be adversely affected by the subcutaneous implantation of n-butyl2-cyanoacrylate or its degrada- tion products as shown by eight different enzymatic, biochemical, or clotting tests. In addition, histological examination of the vital organs revealed that this tissue adhesive when implanted sub- cutaneously apparently causes no observable changes in the liver or other vital organs.

The disruption of hepatic cells with necrosis would be expected to cause increases in the serum levels of LDH, ICDH, SGOT, SGPT, and bilirubin, and in the retention of BSP. However, even over a

28 HOUSTON ET AL

period of 6 months after the implantation of the adhesive, only slight increases of SGPT and partial prothrombin time were noted, and these increases were within normal ranges for the dog.

While further studies on the metabolic and tissue effects of this and other homologs of cyanoacrylate are indicated, the use of n-butyl 2-cyanoacrylate subcutaneously does not appear to be concomitantly associated with hepatocellular damage.

The authors gratefully acknowledge the help of John Hodge for the statistical analyses and Gary Gladieux for his aid on some of the analytical tests.

References 1. John Cameron et al., Surgery, 58, 000 (1965). 2. K. C. Pani e t al., Surgery, 63, 481-89 (1968). 3. F. Leonard, Proc. Physiol. Adhesives, U. of Texas Graduate School of Bio-

medical Sciences, pp. 1-4, February 3 and 4, 1966. 4. R. C. Reynolds et al., ibid, pp. 24-30. 5. J. W. Eichelberger, “Laboratory Methods in Blood Coagulation,” Harper and

Row, 1965. 6. R. Gradwohl, “Clinical Laboratory Methods and Diagnosis,” 6th Edition,

W. B. Saunders Co., 1963. 7. Mallory and Evelyn, “Clinical Diagnosis by Laboratory Methods,” 1. David-

sohn and B. B. Wells, Eds., W. B. Saunders Company, Philadelphia, pp. 547-8, 1962.

Received January 15, 1969 Revised February 23, 1969