Fd Cosmet. Toxicol. Vol. 13. pp. 667-670. Pergamon Press 1975. Printed in Great Britain

Information Section

ARTICLES OF GENERAL INTEREST

POLYMERS FOR THE SURGEON

The tissue-adhesive and haemostatic properties of 2-cyanoacrylates, which polymerize rapidly in contact with water to form powerful seals, have attracted sur- geons for some years. Many studies of the irritancy of these esters and the tissue reactions they induce have been reported (Cited in F.C.T. 1973, 11, 314 & 516).

Cyanoacrylates in skin repair . . . .

Wilkinson (Archs Derm. 1972, 106, 834) has asserted that the important individual characteristics of a cyanoacrylate designed for skin surgery are its cyto- toxicity, the speed with which it polymerizes and the heat generated in the process, and the flexibility or brittleness of the resulting film. The tissue reactions induced by methyl 2-cyanoacrylate (MC) have resulted in its replacement largely by the n-butyl (NBC) and isobutyl (IBC) esters. The cytotoxicity of these compounds appears to depend on their speed of degradation in the tissue, and this decreases with increase in the length of the alkyl chain. An increase in chain length also increases the speed of polymeriza- tion, and this reduces the likelihood of contact of the monomer with adjacent tissues and the consequent risk of irritancy and systemic toxicity. Wetting and spreading, which determine the strength of binding, increase with increasing chain length, but technical problems in connexion with the binding and polymer- ization processes tend to increase with chains of five carbons or more. The optimal chain length seems to be attained therefore with the butyl esters. NBC and IBC can be applied directly or used in conjunction with gelatin film for haemostatic wound dressings for multiple organ injuries and open donor-tissue sites. The formation of IBC film between wound surfaces is undesirable, since it tends to delay fibroplasia and capillary proliferation across the incision and leads to scarring, but NBC and IBC can be used in con- junction with suturing and can eliminate seepage and graft loss when used to secure skin grafts and hair transplants (Wilkinson loc. cit.).

Isoamyl cyanoacrylate (IAC) has been shown to produce greater comfort and less extensive inflamma- tion than IBC when used in the treatment of experi- mentally induced friction blisters in volunteers (Akers et al. Archs Derm. 1973, 107, 544). The best results were obtained by spreading IAC over the raw blister base. Pentyl cyanoacrylate (PC) was more useful when a partially detached skin fragment was to be joined to the blister base, since its polymerization time (3--5 seconds) permitted wrinkles to be smoothed out before setting occurred.

. . . . in fac ia l wounds . . . .

Experimental facial wounds produced by incision 667

of the masseter muscle in rats were covered with gauze or terpolymer sponge and sprayed with IBC by Hunsuck et al. (Oral Surg. 1970, 29, 305). After 5 days the dressing was removed and the degree of healing was examined. At intervals up to 14 days after this, the animals were killed and the tissue in the vicinity of the wound was sectioned for microscopic examination. Wounds that had been protected by a gauze or sponge dressing sprayed with IBC showed little tissue necrosis, dehydration or secondary infec- tion. There were minimal zones of granulation tissue, and the incision appeared to heal faster than either control wounds packed with saline-moistened gauze or wounds packed with terpolymer sponge and sutured. The downgrowth of epithelium was less in IBC-treated wounds than in the controls. Suturing of the terpolymer sponge into the wound induced fas- ter healing and less inflammation necrosis than the control treatment, but was less effective than the sponge-IBC treatment.

. . . . and in ophthalmic surgery . . . .

Evaluation of the effects of MC and IBC treatment after various operations carried out on the rabbit eye by Munton (Expl Eye Res. 1971, 11, 1) has shown that the outcome generally depends on the nature of the repair. In conjunctival repair, good closure and healing occurred; by week 12 the regenerated con- junctiva showed normal numbers of goblet cells, there was a slight increase in vascularity at the limbus and the stroma contained few collagen fibres. Resection of the superior rectus muscle resulted in some early muscle necrosis, with amorphous denucleated areas, fibroblasts and giant cells; after 7 days the limbus showed an increase in vascularity and a reduction in the number of goblet cells. At the muscle end, fibroblasts and fibrin, with ghost denucleated fibres, were seen and were tentatively attributed to the heat of polymerization of the adhesive. In corneal Graefe sections, new blood vessels appeared at the limbus, surrounded by chronic inflammatory cells, but at week 19 the wound had healed, with little vasculariza- tion. The most variable results appeared after kera- toplasty; gross loss of the graft, conical breakdown of the corneal-graft area and staphylomata were seen and vacuolation of the cornea with endothelial meta- plasia to polygonal cells occurred.

Perforated keratotomies, 4-6 mm long, in the rab- bit eye were experimentally joined by direct appli- cation of NBC to the wound area freed from epithe- lium (Giessmann et al. Albrecht v. Graefes Arch. klin. exp. Ophthal. 1972, 183, 294). Three weeks after treat- ment only a thin corneal scar was visible. Histological examination of the wound tissue 5 months later

668 Articles of general interest

showed a little scar tissue but no sign of vasculariza- tion or chronic inflammation.

Spitznas et al. (ibid 1973, 187. 89) applied drops of NBC to the rabbit sclera after conjunctival incision a~d sclerai exposure, in order to attach a fragment of lyophilized dura mater as repair material. No major damage resulted, and the slight conjunctival infection observed was no greater than with alterna- tive procedures; histological examination revealed a mild foreign-body reaction with some multinuclear giant cells and formation of a fibrotic capsule round the adhesive. The procedure was applied successfully in man to the repair of retinal detachment and other conditions involving retinal surgery. In a further study by Spitznas et al. (ibid 1973, 187, 102) the reac- tion of choroid, retina and vitreous was noted in rab- bits after application of NBC. Acute inflammatory round-cell infiltration appeared during the first few days after intrascleral, suprachoroidal or intraretinal application, but the vitreous showed no reaction to an injection of NBC. A mild protracted foreign-body reaction in surrounding tissue followed treatment of the sclera or suprachoroid while late reactions to NBC in the choroid and retina comprised a loosening and atrophy of the tissue, with circumscribed loss of the nuclear zones of the sensory retina~

In vivo degradation of cyanoacrylates

Wade & Leonard (J. biomed. Mater. Res. 1972, 6. 215) treated dogs with sc implants of Ivalon sponge impregnated after insertion with MC labelled with 14C in the C-2 or C-3 position or in the cyano group and determined the activity of various fractions and isolates from the urine collected for 3--4 days after. Urinary urea from animals with the [3-14C]MC-im- pregnated implants was radioactive, while that from the other rats showed little activity. Treatment of pro- tein-free urine with an anion-exchange resin removed 40% of the total radioactivity, but precipitation with barium hydroxide did not. No activity could be found in distillates from urine acidified with sulphuric acid. Approximately 55~o of the urinary metabolites of MC appear to be neutral compounds. The results indicate that random chain scission of MC occurs, with pro- duction of formaldehyde, but attempts to discover radioactivity in the form of formic acid were unsuc- cessful.

Absorbable polymer sutures and other implants Various polymers have featured in the continuing

search for materials ideally suited for use as absorb- able sutures. A copolymer of lactide and glycollide (cyclic intermediates derived from lactic and glycollic acids) intended for use as a surgical suture material was embedded by C o n n e t al. (Am. J. Surg. 1974, 128. 19) in the rectus sheath and muscle of rabbits for up to 60 days. Minimal acute inflammatory changes, a small amount of necrotic exudate, minimal giant-cell reaction and a small development of adja- cent granulation tissue were apparent after 5 days. This reaction appeared to be no greater than that provoked by the trauma of suturing. No granulation tissue could be seen after 15 days. After 30 days there was no evidence of any necrotic exudate surrounding the suture. Gross inspection of the wound after 60 days failed to distinguish the suture, and microscopic examination showed an absence of giant cells, mononuclear cells and eosinophils. This copolymer (known as polyglactin 910 or Vicryl, from Ethicon, Inc., Somerville, N.J.), therefore appears to be devoid of toxic properties under the conditions of this exper- iment.

Implantation of blocks of 14C-labelled polylactic acid in the abdominal wall of rats resulted in little distribution of radioactivity in tissues and organs (Brady et al. J. biomed. Mater. Res. 1973, 7, 155). The implant lost about 36"8~o of its activity during 168 days. Of this about 29"4~o appeared in expired carbon dioxide, 4"6~ in the urine and 2"8~o in the faeces. Cells that invaded the implant possessed either large double-walled vacuoles or large accumulations of mitochondria and microvesicles. It appears that this type of polylactic acid implant is well tolerated by the host tissue. The material persisted at the im- plantation site for about 1.5 years, however, in this experiment. While prolonged persistence of an im- plant might be useful in some circumstances, in others it could delay complete healing, and attention is drawn to the possibility that resorbable implants of this type might be modified by incorporation of other resorbable materials, such as polyglycollic acid. so that they could be 'tailor-made' in respect of both strength and resorbability for a variety of clinical applications.

[P. Cooper--B1BRA]

DEALING WITH ACETALDEHYDE

Acetaldehyde is formed in the body as a metabolite of ethanol and is also an important constituent of tobacco smoke. Previous studies have shown that this aldehyde is retained in the upper respiratory tract after inhalation (Cited in F.C.T. 1973, 11. 922), and that it causes biphasic changes in blood pressure when given by iv injection (ibid 1974, 12, 787). The presence of ac.etaldehyde produced by microbiological activity in home-brewed lager has caused gastric ero- sion (ibid 1972, 10, 435).

Metabolism and distribution

The distribution of acetaldehyde in the brains of rats following a single dose of ethanol has been stud-

ied by Sippel (J. Neurochenl. 1974, 23. 451). An ip injection of 65mmol ethanol/kg was given 30 minutes before tissue sampling. Brain tissue, exclud- ing the pons--medulla, cerebellum, olfactory lobes and lateral parts of the cerebrum, was taken in the frozen state, treated with thiourea to prevent non-enzymic oxidation of ethanol, and assayed for both acetalde- hyde and ethanol by gas-liquid chromatography. Cere- bral blood contained I03--360nmol acetaldehyde/ ml, but there was no significant acetaldehyde con- centration in the brain tissue when the cerebral blood concentration lay below 250nmol/ml. The lactate/ pyruvate ratio in these tissues gave no indication of ischaemia, so that the absence of acetaldehyde could