A new system of treating wounds by a continuous topical application of medication

British Journalof Plastic Surgery (1990), 43,83-87 Q 1990 The Trustees of British Association of Plastic Surgeons

0007-1226/90/0043-0083/$10.00

A new system of treating wounds by a continuous topical application of medication Y. SAWADA,

T. YOTSUYANAGI,

I. HATAYAMA

and K. SONE

Departments of Plastic and Reconstructive Surgery, Second Biochemistry, and Pharmacy, Hirosaki University School of Medicine, Japan

Summary-A new procedure using a silicone gel sheet that enables the continuous topical application of a drug to a wound, and the effect of this therapeutic procedure on experimental skin flaps of rats, are described. Although a silicone gel sheet without a drug did not augment the flap survival length, silicone gel sheets containing Prostaglandin E 1 (PGE 1) and Ofloxacin showed significant elongation of the survival length of the flaps without signs of infection. Similarly, silicone gel sheets containing PGE 1 inserted under the flap, like a drain, also showed statistically significant augmentation of the flap survival length. These facts showed a therapeutic potential of this new silicone gel sheet containing a drug.

It has been pointed out that certain drugs can influence wound healing (Peacock, 1984). Usually, in the experimental model, such drugs have been administered systemically because continuous topical application was difficult (Suzuki et al., 1986, 1987). We have tested a new continuous topical administration system for such drugs, namely Ofloxacin (OFLX) and Prostaglandin El (PGEI), to see if they could be effectively delivered to experimental flaps.

raised and then sutured tightly back into position. In group E, however, only three points on each side of the flap were sutured to the skin so as to keep small raw areas exposed (Fig. 1). In group A the flaps were elevated and immediately sutured tightly in their original sites. These rats served as controls. In group B, after elevation and suturing of the flap, OpSitea was applied after the flap had been sutured back in place. In groups C to E, each flap was covered with a silicone gel sheet measuring 3 by 14 cm and 2 mm thick, which was sutured onto the dorsum to cover the entire flap (Fig. 2). The flaps in group C were treated with a silicone gel sheet that contained only OFLX, and groups D and E were treated with a silicone gel sheet that contained both OFLX and PGEl. In group F, the silicone gel sheet, cut 10 x 0.5 cm in size and 2 mm thick, was inserted and sutured under the flap in a similar manner to the insertion of a drain (Fig. 3). The groups are summarised in Figure 4. On the seventh day after surgery, the silicone gel and the OpSite which covered the flap were removed, and on the next day the flap survival areas were assessed and measured by using a planimeter, in accordance with the method of Roth et al. (1988). Student’s t-test was employed to assess the differences between the mean flap survival rate of each test group and the control group. Further, the finely structured vascularisation in the flaps of each group was observed according to the procedure of Kami e? al. (1985).

Materials and methods The silicone gel sheeting set used was provided through the courtesy of Dow Corning Japan (Tokyo). OFLX was provided by Daiichi Seiyaku (Tokyo) and the PGEl by Taisho Seiyaku (Tokyo). The preparation and characteristics of the silicone gel sheet containing OFLX have been described previously (Sawada et al., 1990). PGEl and OFLX can be easily mixed in the silicone gel sheet. The concentration of the OFLX used was 0.027& and in the groups in which OFLX was combined with PGEl, the concentration of the PGEl was 1O-5% (10 micrograms in 100 grams of silicone gel). The two types of premeditated silicone gel sheets were then stored at 4°C until use. Sixty female Hirosaki hairless rats, weighing from 250 to 300 grams, were used. Six groups of 10 rats each were designated as groups A to F. On the back of each rat, a skin flap including the panniculus carnosus, caudally based and 9 x 2 cm in size, was 83

84

Fig. 1

Fig. 2

Figure 1-A caudally based skin flap, 9 x 2 cm, elevated and sutured back in position. In group E the flap was sutured at three points on each side to keep small raw areas exposed. Figure 2-In groups C to E the flaps were wholly covered with a silicone gel sheet as shown. Figure Sin group F a strip of thin silicone gel sheet including OFLX and PGEl was inserted under the flap, like a drain.

Results By the seventh day after surgery, none of the rats treated with the silicone gel sheets showed any infection. However, in group B five rats treated by OpSite showed a purulent discharge and these five rats were excluded from this survey. The mean surviving areas of the flaps were as follows: in group A (control group) 49.8 f 5.2 cmZ (mean f SD.); in group C 52.4 k 4.0 cm2 ; in group D 67.2k6.5 cm2; in group E 61.9k6.2 cm?; and in group F 69.7 + 6.2 cm2. The survival rate of the five remaining flaps in group B was 47.5 + 3.5 cm2 (n= 5) (Fig. 5). Compared with control group A, groups D to F showed a statistically significant increase in the survival rate (p < 0.01, respectively). There were no significant differences between groups A, B and C. Vasculature of the flaps

Compared to the control group, the fine vasculature seen in the flaps of groups D to F, which had received PGE 1, was remarkable. In these flaps the vascular networks had increased both within the skin and around the flap. The vascular communi-

cation also had increased between the surviving area of the flap and the surrounding tissue. In group F especially, in which the inserted silicone gel sheet was beneath the flap, a remarkable vascular increase in the flap was noted. In groups A, B and C there were no remarkable differences, although a mild increase of vasculature was recognised in the flap of group C (Fig. 6). Discussion Although it is considered doubtful that the results achieved in animal experiments accurately predict clinical efficacy (Kerrigan and Daniel, 1982), experimental skin flaps using the rat are practical models to investigate wound healing. Further, the success of drugs to improve experimental skin flap survival is dependent on the characteristics or the mode of action of the test drugs. In this regard, prostaglandins administered systemically have been shown to have a beneficial effect, in some laboratories (Roth et al., 1988). The mode of action of PGEl is vasodilation and the inhibition of platelet aggregation (Suzuki et al., 1987). Although prostaglandins are usually administered systemi-

A NEW SYSTEM OF TREATING

Covering Drugs

Group A none none

WOUNDS

BY A CONTINUOUS

TOPICAL

‘-B Y Group B Op-Site

Grou);\C Silicone gel OFLX

APPLICATION

Group D Silicone gal OFLX, PGE 1

OF MEDICATION

Group E Silicone gel OFLX, PGEl

85

Group F none OFLX, PGE 1 Silicone gel beneath the flap

Fig. 4

Flap Survival Rate (%)

P
P
P
Necrosis 80

60

Survived area

1.8f 5.2

iroup B 47.5k3.5

Group C 52.4k4.0

Group D 67.2k6.5

Fig. 5 Figure 4-The

groups.

Figure SThe

flap survival

rate in each group. For details,

see text.

Group 61.9k6.2

69.7k6.2

86

BRITISH JOURNAL

OF PLASTIC SURGERY

Fig. 6 Figurea&-The the va sculature the flaps

fine vasculature of the flaps in rats from groups A, C. D and F. The flaps in D and F show a remarkable increar ie of compared to the flaps in A and C. “9” shows the base of the flaps and arrows show the area that survived in eat :h of

tally in clinical practice and in experimental models (Emerson and Sykes, 198 1; Sasaki and Pang, 198 1; Suzuki et al., 1986, 1987) the major portion of the systemically administered PGEl would be quickly metabolised in the lung, so that its effectiveness would be of short duration, and only a small portion of the administered PGEl would be distributed to the flap (Sano et al., 1985). Moreover, systemically administered PGEl cannot reach the flap tips, which soon turn necrotic due to poor circulation, as has been seen in experimental models. In contrast, Sano et al. (1985) have shown that a topical administration of PGEl mixed with vaseline is effective in augmenting the flap survival length at a lower dose than systemic PGEI. Also, topical PGEl gave fewer adverse drug reactions than systemic. However, the topical administration described by Sano et al. (1985) had demerits in that the administered drugs did not reach the affected tissue

effectively as most of the drug was adsorbed to the dressing material. A constant release of the drug from the ointment was found difficult to achieve. Further, the Vaseline used often blocked the wound and caused wound infections. Moreover, frequent application of the ointment is troublesome to the physician and painful to the patient. The new procedural approach described here enables continuous delivery of the drug to the wound, with little risk of wound infection. In a previous experiment, our silicone gel sheet preparation released the contained drug continuously for 2 weeks without change of the silicone gel, and direct inspection of the wound was possible through the transparent gel sheet (Sawada et al., 1990). The PGEl mixed into the Vaseline loses its efficacy by only 2.2% when stored at 5°C for 672 days, and by 37.1% when stored at 40°C (Sano et al., 1985). McGrath (1981) has mentioned that a moist environment augments survival length in a vascu-

A NEW SYSTEM OF TREATING

WOUNDS

BY A CONTINUOUS

lar-compromised skin flap. Similarly, a silicone gel also provides the wound with a moist environment (Quinn, 1987). It must be stated, however, that covering our experimental flaps with silicone gel without PGEl, as in group C, did not improve the flap survival length significantly. Sasaki et al. (1979) pointed out that tightly sutured flaps covered only with a water-impermeable film did not improve the survival length of the flap. Further, although we had suspected that our group E rats, which had a small raw surface bordering the flap, would show an improved flap survival length compared to the flaps in group D, we could not find any significant difference between them. This may be because the PGEl was administered to the flap mainly through the skin of the flap. Moreover, rapid contraction of the wound might have impeded the drug absorption through the wound. Covering the wound tightly with silicone gel can be considered an occlusive dressing technique that accelerates the transdermal absorption of the drugs. It has been shown that silicone oil constantly released from the gel sheet accelerates wound healing in the treatment of burn patients (Miller er al., 1965; Spira et al., 1967; Weeder ef al., 1967; Batdorf et al., 1969; Helal er al., 1982). Although there was no significant increase in the flap survival length in flaps covered with OpSite or silicone gel without PGEl, flaps treated with silicone gel containing only OFLX showed no infection compared to the flap treated with OpSite. From our findings, we feel that this technique of topical, continuous administration of medication is useful in wound healing and that further application of this technique should be undertaken in clinical practice. Acknowledgements The authors wish to thank Dow Coming Japan, Daiichi Seiyaku and Taisho Seiyaku, Tokyo, for supplying the medication used in this study. Dr Mitsuo Sugawara, Professor, Department of Plastic and Reconstructive Surgery, Hirosaki University School of Medicine, is also acknowledged for his helpful advice in the preparation of the manuscript.

References Batdorf, J. W., Cnnunack, K. V. and Coloquitt, R. D. (1969). The silicone dressing management of the burned hand. Archives of Surgery, 98.469. Emerson, D. J. M. and Sykes, P. J. (1981). The effect of prostacyclin on experimental random pattern flaps in the rat. British Journal of Plastic Surgery, 34,264. Helal, B., Chapman, R., EBia, M. and Giord, D. (1982). The use of silicone oil for mobilisation of the hand. Journal of Bone and Joint Surgery, 64B. 67.

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APPLICATION

87

OF MEDICATION

Kami, T., Yu&inutrn, Y., Nakajhna, T., Ohshiro, T. and F@nu, T. (1985). Effect of low-power lasers on flap survival. Annals ofPlastic Surgery, 14, 36. Kerrignn, C. L. and Daniel, R. K. (1982). Pharmacologic treatment of the failing skin flap. Plastic and Reconstructive Surgery, IO, 541. McGrath, M. H. (1981). How topical dressings salvage “questionable” flaps: experimental study. Plastic and Reconstructive Surgery, 67,653. Miller, J., Hardy, B. and Spira, M. (1965). Treatment of bums of the hand with silicone dressing and early motion. Journal of Bone and Joint Surgery, 47A, 938. Peaeoek, E. E. Jr. (1984). Wound Repair. 3rd Edition. Philadelphia: W. B. Saunders,p. 102. Quinn, K. J. (1987). Silicone gel in scar treatment. Burns, 13S, 33. Roth, A. G., Brigga, P. C., Jones, E. W. and Heckler, F. R. (1988). Augmentation of skin flap survival by parenteral pentoxifylline. British Journal of Plasiic Surgery, 41,5 15. Smo, S., Tajima, S., Toyuda, T. and Hira, M. (1985). Effects of externally applied prostaglandin El on skin flap survival. Journal of Japan Society of Plastic and Reconstructive Surgery, $7. Sasaki, A., Fukuda, 0. and Soeda, S. (1979). Attempts to increase the surviving length in skin flaps by a moist environment, Plastic and Reconstructive Surgery, 64,526. Sasaki,G. H. and Pang, C. Y. (1981). Experimental evidence for involvement of prostaglandins in viability of acute skin flaps: effects on viability and mode of action. Plastic and Reconstructive Surgery, 67, 335. Sawada, Y., Suzuki, T., Hatayanta, I. and Sane, K. (1990). Silicone gel including antimicrobial agent. British Journal of Plastic Surgery, 43, 78. Spira, M., Miier, J., Hardy, B. and Gerow, F. J. (1967). Silicone bag treatment of burned hand. Plastic and Reconstructive Surgery, 39, 357. Suzuki, S., Id&i, N., Ogawa, Y., Hiramoto, M. and Fujimori, R. (1986). The effects of intravenous PGEl on clinically critical flaps. JournalofJapan SocietyofPIasticand Reconstructive Surgery, 6,933. Suzuki, S., Isshiki, N., Ogawa, Y., Nishimura, R. and Kurokawa, M. (1987). Effect of intravenous prostaglandin El on experimental flaps. Annals of Plastic Surgery, 19,49. Weeder, R. S., Brooks, H. W. and Buyer, A. S. (1967). Silicone immersion in the care of bum. Plastic and Reconstructive Surgery. 39,256.

The Authors Yukintasa Sawada, MD, Associate Professor, Department of Plastic and Reconstructive Surgery Takatoahi Yotauyanagi, MD, Resident, Department of Plastic and Reconstructive Surgery Ichiro Hatayama, MD, Assistant Professor, Department of Second Biochemistry Ken Sone, MD, Research Instructor, Department of Pharmacy Hirosaki University School of Medicine, City, Aomori Prefecture 036, Japan. Requests

for reprints

to Dr Sawada

Paper received 21 April 1989. Accepted 22 June 1989.

53 Hon-cho,

Hirosaki

at the above address.