Zoografting: A curious chapter in the history of plastic surgery

ZOOGRAFTING: HISTORY

A C U R I O U S C H A P T E R IN T H E OF P L A S T I C

SURGERY 1

By THOMAS GIBSON, M.B., F.R.C.S.(Ed.)

Plastic Surgery Unit, Glasgow Royal Infirmary " It is to be hoped that this is the last we shall hear of an operation which should never have been introduced." mBritish Medical Journal, 1887. WHEN a portion of living tissue is taken from one animal and grafted on to another of a different species the term used for such a transplant is "heterograft." A " z o o g r a f t " is a heterograft in which the host or recipient is a human being. The term is restricted to living transplants and does not include such preserved animal matter as catgut, ivory, bovine cartilage, or kangaroo tendon. As far as I know, the first reference to such a graft is to be found in the Observationes Medico-Chirurgic~e of Jobus a Meek'ren (1682), where the writer tells of a letter received by a Dutch theologian named Engebert Sloot from a Russian colleague, Johan Kraanwinkel. In this letter Kraanwinkel recounted the tale of a Russian nobleman whose head had been cleft by a Tartar's sword so that not only scalp but parts of the skull had been lost. This loss was successfully repaired by a surgeon with a piece of bone taken from the skull of a dog, and the nobleman, overjoyed, told all his friends of the miraculous cure. But the story reached the ears of the head of the Russian Church, who, taking a different view of the case, threatened the nobleman with excommunication and denied him access to any church " so long as the particles of bone from the dog's head were allowed to remain fixed to the bones of the head of a Christian man. The nobleman, preferring to be numbered among the members of the church than to suffer anything for a true healing, ordered the surgeon to take away the fragments of dog's bone; and so . . . he escaped the full force of the excommunication." The main interest of this third-rate anecdote lies in the attitude of authority as represented by the Church and the power which it wielded. The dead ecclesiastical hand smothering original thought was a familiar phenomenon of this era in both science and medicine, and little further was heard of zoografting until the second half of the nineteenth century. This was the golden age of surgical opportunism when the twin innovations of anaesthesia and antisepsis had opened up a new and extensive range of possible techniques. There were many real advances, but much that was tried and enthused over was later discredited and discarded. Zoografting was a typical example. A variety of animal tissues were transplanted. Peyrot (I886) took a tendon from the hind paw of a young dog and used it to replace a flexor tendon in the finger of a boy. The tendon " t o o k " in so far as it was not extruded later, but the movements of the finger were poor. McGill (1889) used successfully the femur from a freshly killed rabbit to bridge a defect in a human radius. Perhaps the most astonishing claim of all was that of Bradford (I887), who reported that he 1 A paper read to the Scottish Society for the History of Medicine on Ixth November I954. 234

ZOOGRAFTING: A CURIOUS CHAPTER IN THE HISTORY OF PLASTIC SURGERY 235 had transferred a rabbit's eye into a human orbit and that the eye still retained its vitality after two months ! Skin was, however, the animal tissue most widely employed, and it is with skin zoografts that this essay is chiefly concerned. Apart from their intrinsic interest, the papers written on this subject are the records of a series of experiments which can never be justifiably repeated. Although many of the writers wrote with extravagant and misplaced enthusiasm, and although even the best observers described as successful " t a k e s " what, in fact, we now know to be failures, it is of great interest to see why they were mistaken and, in the light of present-day knowledge, to understand how completely erroneous deductions were made from accurately recorded facts. There are two categories of skin grafts, pedicled grafts and free grafts, and animals have been used to supply both; but since they differ fundamentally in technique and behaviour they will be treated separately. A pedicled skin graft is one in which the graft is only partially detached before being applied to its new site ; it thereby retains enough of its original blood supply to maintain vitality while fresh blogd-vessels grow into it from the new bed. After some weeks it can be completely detached with safety. The difficulties of using an animal as the donor of such a graft are fairly obvious, the greatest being that of keeping the animal and the human patient firmly fixed together in bed for a period of three weeks or more. But one or two hardy surgeons made the attempt, encouraged no doubt by some evidence from what we would now call parabiosis experiments between animals of different species. Paul Bert (i863) , for example, united a rat to a cat on six occasions, and although none of the results was permanent he was convinced that adhesion was possible and that vascular communication between the animals occurred ; atropine instilled per rectum in the cat caused dilatation of the rat's pupils some time later. A more striking example of the same thing was reported in the Scarboro' Mercury of 186o by a Mr Wainde, " surgeon of Kirby Moorside," who claimed to have united a crow and a rat. He first made a raw area on the back of the rat and a similar one on the breast of the crow ; then having mounted the crow astride the rat he bound them together. Healing occurred and he wrote : " They now present a most peculiar appearance and do not seem by any means disposed to part company. The crow scarcely possesses power of wing sufficient to raise its companion far from the ground, though it flutters along at the height of a foot or two for several yards." It is only fair to add that the cutting from the newspaper was sent by a correspondent signing himself " Misericordia" to the editor of the Medical Times and Gazette of I86O, where it was reprinted under the heading of " Physiological Cruelty " and where, incidentally, it has been preserved for posterity. From these and similar experiments it was apparent that temporary adhesion at least was possible between different species. S6dillot (1868) was the first surgeon to try to obtain adhesion of a pedicled graft from an animal to a human patient. He used as a flap the hairless skin from the abdominal region of a dog (un chien danois), but gave no clinical details of the patient although it is implied that it was a case of extensive skin loss from a hand. The union failed because of the " excessive and continual movements of the animal." He suggested, however, that " i t is an experiment which might be done again with the precaution of dividing the spinal cord below the respiratory nerves in order to paralyse the greater part of the movements without causing death."

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The most striking report of this method of zoografting is to be found in the

Boston Medical and Surgical ffournal of 188o, and as an example of the bizarre in surgical technique it deserves quotation in full. In the issue of 9th September 188o the Chicago correspondent of the Journal wrote as follows: " The topic in professional circles here at present is the operation, at the County Hospital, by Dr E. W. Lee, of transplantation of skin from the sheep to the human body. What now adds to the interest of the operation, and makes those who have watched the progress of the study and trial with anxiety hold their breath, is the fact that the experiment bids fair to be a success. The subject of this experiment (that is the human subject) is a girl about IO years of age who sustained an extensive burn on the back a year and a half ago. A large granulating ulcer remains, despite all efforts to induce healing. Skin grafting has been faithfully practised, but without success. The child has, of course, been obliged to lie prone most of the time, and has become greatly reduced. A few weeks ago an attempt was made to transplant a flap from the thigh of her older brother, but the flap sloughed. That failing, Dr Lee began at once to experiment with flaps and dissections from the sides of sheep. His first subject, a lamb, nearly full grown, was lost, soon after the dissection of the flap, from the shock of the operation. He next operated on two other lambs, dissecting up two moderate-sized flaps from each, placing oiled silk beneath them to prevent adhesion, and dressing them antiseptically. These animals were then turned out to grass in the hospital yard, and were also fed on milk, with occasionally a small admixture of whisky. They took to this diet with avidity. After several days--nearly two weeks--had elapsed, and the animals were vigorous, the operation of the application of the flaps of one of them was made. A new flap was dissected from between the two already made, and applied in the same manner as the others. The new flap has made a firmer adhesion than the old ones. The lamb is fastened in the standing posture, in a wood cage, its body being securely fixed and sustained by plaster of Paris bandaging of its limbs and quarters. Perfect coaptation and perfect immobilisation are secured. The patient has improved in appearance and general condition since the operation, and the lamb shows no signs of failing health. " The coaptation of the three large flaps from the side of the lamb to the ulcer on the patient was made on the 24th of August. Six days have elapsed at this writing, and union of all the flaps seems to be perfect. Of course, when they come to be separated from the lamb they may suffer and perhaps slough, but it is now well settled that the skin of the sheep will adhere to a granulating surface on the human body." As an example of " rushing into print " this can rarely have been bettered. Fortunately, the Chicago correspondent gave the sequel to this piece of news in his next dispatch on 7th October r88o as follows : " The experiment of Dr Lee at the County Hospital of transplanting the flaps of skin of the sheep to the body of a little girl failed by the death of the patient before the flaps were completely cut loose from the body of the sheep. At the autopsy it was found, however, that the flaps were all firmly adherent, and were capable of being nourished from the body of the child. The death of the latter was due clearly to exhaustion and to amyloid degeneration of the liver, kidneys, and other organs. Dr Lee next attempted to cause a sheep flap to adhere to a large ulcerating surface from which an enormous epithelioma had been removed.

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The patient was a man and in fair general condition, the ulcer being upon the outer aspect of the thigh. The difficulties of maintaining immobility of the patient and the sheep were greater than in the first instance, and although adhesion of a part of the flap took place it was lost in its removal from the animal. A third trial has been made in a case of a large ulcer of the leg, left after the extirpation of an angioma, but the soil is unpromising, and no very sanguine hopes of success have been entertained. The trial is still in progress." After a prolonged search no trace has been found of Dr Lee having ever written about his experiments, and presumably his surgical zeal was directed later into more profitable channels. From our present knowledge of the reaction of an individual to a heterograft of this kind it seems possible that such a flap could adhere and could survive after being separated from the donor animal, but survival would be a matter of days only, and necrosis of the whole flap would inevitably ensue. No later example of this form of zoografting has been found in print, although rumour has it that the attempt has been made on more than one occasion but with no more successful outcome. Free skin grafts are those which are wholly separated before transplantation and which depend for their success on the ability of the cells to survive until such time as a new blood supply reaches them from their new site. Reverdin was the first to popularise the procedure although there were a number of recorded free skin grafts before his time. His paper, delivered to the Socidt6 Impdriale de Chirurgerie in December 1869, received a mixed reception, being deemed by some unjustifiable or of no importance ; but free skin grafting had come to stay. Pollock introduced it into England in the following year, and the medical journals of 187o contained many references to the new technique. Reverdin's second paper on the subject was read to the Acad6mie des Sciences in 1871, and on this occasion he said that skin for grafting could be taken not only from the same individual but from individuals of the same species or of different species. Here, then, was authority for zoografting coming from the highest source. Within a year a paper was read to the Acaddmie des Sciences by Coze (1872) following Reverdin's suggestion and reporting three cases of obstinate leg ulcers healed by skin grafts from rabbits--a paper which so impressed the Acaddmie that they referred it to the Committee for Prizes in Medicine. In this way the era of free skin zoografting began. The pinch grafting procedure of Reverdin was too minor to warrant the still dangerous general anmsthesia of the time, but " t h e snip " was sufficiently painful to be disliked by the patient. (Local anaesthesia for the purpose was first reported by Dum6nil in I89O.) Nor were volunteer donors very willing to come forward. Skin from the lower animals, therefore, fulfilled a definite clinical need, and the list of donors includes dogs, cats, rabbits, rats, and pigs among the mammals, chickens, cockerels, and pigeons among the birds ; and, most popular of all, the frog. Frogs were plentiful, cheap, and easily obtained. The skin did not carry troublesome appendages like hair, fur, or feathers. Admittedly it was pigmented, but this seemed of no consequence since it was noted that after some days the pigment disappeared. Allen (1884) wrote : " I find that grafts from a decapitated frog make grafts which admirably answer all purposes, forming a source of supply always at hand in the country except during the winter months, being easily

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applied on account of their uniformity in thickness and necessitating no pain to suffering humanity. The skin of a single frog yields grafts for an enormous extent of surface and preserves its vitality so long that if the patient is at a distance the portion of skin can be carried by the surgeon in his pocket for an hour or more without injury, provided it is wrapped up in gutta percha or other waterproof tissue to prevent drying." The frog was not always killed first. Fowler (1889) had an assistant hold it by the extremities and head, while hc cut strips of skin from it. " The length (of the strip)," hc wrote, " w i l l be governed by the steadiness with which the animal is held by the assistant." Hc reported a case in which frog skin and human homograft skin had been used to resurface the raw area rcsulting from an extensive burn. Chronic granulating ulcers resulting from burns or other causes were, in fact, the usual recipient sites of frog skin grafts, although Fillet de Grandmont (189o) used them to correct a severe ectropion in a child. The record for the largest series treated by frog's skin must be held by Ranking, who claimcd to have used it with good results in between three and four hundred paticnts. His letter to the editor of the Lancet in 19o6, at which time he was a retired lieutenant°colonel of the Indian Army, is worth quoting in part. It is typical of the uncritical, illogical writing which characterises many of the reports on zoografts and of the complete lack of informative answer to the one question wc would like answered : " What exactly happened to the graft ? " Ranking commented first on a case reported in the press of a severe burn in which skin grafts had been obtained from the arms, legs, and backs of the patient's son, husband, and mother-in-law, the local coroner, the doctor, and three nurses, and suggcstcd that the excellent results to be obtained from frog skin grafting were not sufficiently known ! He continued : " M y first use of it was in my own case. I had suffered for nearly three years from obstinate ulceration of the skin of the foot which had resisted all treatment and steadily refused to heal. When I mention that I consulted several eminent surgeons, among them the late Sir James Paget and the late Sir William Lavory, it will be recognised that I had the best advice obtainable. To make a long story short, I commenced using grafts of frog skin in the middle of January I885, and in less than six wecks had a sound covering of skin. At the present time more than twenty years have elapsed, the cicatrix is perfcctly sound and has none of the puckering and stiffness so often seen in cicatrices when human skin has been used. In fact it is impossible, without close examination, to scc the cicatrix at all, and yet the ulcerated surface extended over the dorsum of the foot round under both malleoli, and there was only a bridge of skin about two inches in width left at the back of the foot. I was so encouraged by this result that I used frog skin in every case of the kind after that, and, at a rough estimate, must have used it in three or four hundred cases in all with good results at the time, and I doubt not with cqually pcrmancnt effects." Many animals besides frogs were used. Two writers, Masterman (1888) and Rcdard (1888), mention that the idea of frog's skin was repulsive to their patient and they made use of wild young rabbits and chickens respectively (which one might have thought equally repulsive). Alexander Miles (1889) read a paper to the Edinburgh Medico-Chirurgical Society on a case in which he had transplanted full-thickness skin from the abdomen of a young greyhound to an ulcer resulting from a burn of the leg. " On dressing after three days," he wrote, " o n l y

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one small graft was found to have failed to take. Cicatrisation went on rapidly from the grafts and also from the margins of the ulcer and in six weeks the whole leg was covered with a strong cicatrix with practically no contraction. It is now over three months since the patient was last under treatment and he is attending school and in perfect health. It may be added that there is as yet no evidence of the reproduction of hairs and no secretion from the skin, but the sensation of the cicatrix is quite as good as that of other parts of the limb." A few years later Miles (1895) wrote a longer report on ten cases of grafts from the lower animals in which he had used frogs, rabbits, kittens, greyhound pups, and a fox-terrier pup. Of these cases four were entirely successful, four partially, and two failed. Miles tried other grafting materials including peritoneum and circumcised prepuces, but was not quite so enterprising as a German professor named W61fler who was reported by the Berlin correspondent of the British Medical Journal of 1888 as follows: " After having excised the thickened and indurated tissues from impermeable urethral strictures, he transplanted mucous membrane from a prolapsed uterus. The operation was completely successful. In the same manner he transplanted mucous membrane from a prolapsed rectum on to the conjunctiva in a case of blepharoplasty. He succeeded even in transplanting mucous membrane from frogs, pigeons, and rabbits with good results." There was a tendency to use hairless skin where possible. Van Meter (189o) obtained his grafts from puppy dogs of the Mexican hairless breed. In the early years pigs were used, but later the antivivisection laws (1876) made it necessary to kill the pig, which, according to Miles (I895), made pigs too expensive. Raven (1877) wrote of the case of a little girl with a granulating surface resulting from a burn and said that having used 3oo grafts of her own skin he had exhausted the supply, whereupon he had recourse to a young pig. " I can now see my way," he writes, " t o a successful termination of the case provided I am not interfered with by the Society for the Utter, Total, and Immediate Suppression of Vivisection. I am not forgetful of the sorrows of the pig ; but he suffers in very good company, most of his fellow victims being Sisters of Mercy." Watson Cheyne (189o) wrote that he had succeeded in getting growth from the skin of frogs and of white rats, but that he had failed with kittens, although the areas on which he had put the grafts were not very suitable. There are a few scattered references to skin from birds. A French surgeon named Redard (1888) used skin from the under surface of a chicken's wing. Aldrich (I893), an American, took the grafts from half-grown pigeons, or squabs as he called them. Altramirano (I888), in South America, used cock's gills which he split open and divided into small pieces. But the presence of feathers seems to have restricted their use. It would be tedious and uninteresting to list all the papers which have been published on the subject, most of which can be obtained from the Catalogue to the Library of the Surgeon-General's Office. Those that have been mentioned give a reasonably representative picture of the different animals and the various procedures. There was never any exposure of the fallacies of this method of skin grafting, never any denunciation of what was a most inferior mode of treatment. Towards the end of last century the references to the procedure became fewer, and, apart from the work of Voronoff (1925) on "rejuvenation" by testicular transplants from various animals, little has been written about it since. The introduction of local anmsthesia, the improvements in general anmsthesia, and the

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advent of a saner and perhaps more conservative attitude to clinical experimentation seem to have been the main factors in bringing to an end a rather colourful procedure. In retrospect, two questions remain to be answered. What did these writers expect to happen to their grafts, and what did, in fact, happen to them ? It seems almost unbelievable that surgeons should have expected zoografts to survive as such with sheep's wool, dog's hair, or rabbit's fur growing from the patient, and accompanied no doubt by the appropriate body odour. Yet some were prepared for just that (see the reference to Miles (1889) above). In mitigation it must be noted that in the early days of free skin grafting there was considerable confusion about the behaviour of the grafts, particularly about whether they grew or not. Those who held that they did not grow (and Reverdin in his second paper (1871 ) subscribed to this view) believed that the graft acted by contact on the surrounding granulations which became changed into epithelium. Zoografts could therefore be used in the same way, not as entities which would proliferate and grow, but merely as stimulants to epithelial metamorphosis of the granulation tissue. A few histological sections would soon have settled the problem, but there was a disinclination to spoil a healed ulcer for the sake of academic knowledge. Miles, asked about this as late as 1895, said that " t h e r e was no microscopic preparation because nobody wished to tear up that which he had just got successfully healed." One further theory about skin growth after grafting illustrates the confusion of thought of the time and may be mentioned here. Writing of frog skin grafts, Allen (1884) said : " My friend and former teacher, Chief Professor Clelland of Glasgow (he was Professor of Anatomy--author), long ago suggested privately to me and, subsequently, I believe, in 1877, to his class, that in his opinion the process of healing by skin grafting forcibly demonstrated the correctness of Stricker's view of the existence of sexes in the tissues. The colonies of epithelial corpuscles at the edges of the ulcer remain quiescent through lack of one sexual element, which the grafts no sooner supply than reproduction rapidly sets in, fertilisation being probably brought about through the medium of the fluid which bathes the surface of the granulations. If the sexual theory accounts for the process, the skin that grows after the application of the frog grafts must be of a new breed, a cross between human and frog epidermal elements." What was the fate of these grafts ? We now know that while grafts from another individual, of the same or different species, may " take " for a short time and may even acquire a blood supply from the host, a systemic reaction to the foreign tissue develops after a short but variable period of time and leads to the necrosis and dissolution of all cellular elements in the graft. All zoografts were failures, therefore, in so far as permanent "takes " were never achieved, and indeed there is no record of such embarrassing animal appendages in the literature. It is, however, only the cellular elements of the grafts which are destroyed in the first instance. Experience of the analogous method of homografting, i.e., using skin from another human being, shows that while the epithelium is shed there frequently remains behind a thin film of connective and elastic tissue fibres. This wraith-like remnant of the former graft is held in place by the granulations and may, in fact, become overgrown by host epithelium, but it is eventually removed by phagocytosis (Gibson and Medawar, 1943).

ZOOGRAFTING: A CURIOUS CHAPTER IN THE HISTORY OF PLASTIC SURGERY 2417 The same thing seems to have happened with zoografts, but was not recognised for what it was. Those who took the trouble to observe and record the behaviour of frog skin noted that the pigment disappeared early. Petersen (1886) noted that pigmentation disappeared after six days, Smith (1895) after five to ten days; Fowler (1889) described the graft as " perfectly diaphanous and resembling wet tissue p a p e r " when the colour faded after seven to ten days ; DebousquetLaborderie (1886) noted in one case that the pigment remained for nine days, after which it resembled " un papier ~ cigarette mouill6." Since the pigment cells in the frog lie in the basal layer of the epithelium it is fairly obvious what happened : the epithelial cells were shed, leaving behind the transparent film of dermal remnants. The same thing was noted with furry animals, and Miles said that it was unnecessary to shave them since the hairs came away after a few days, evidence of the epithelial death which had just occurred. After a very few days, therefore, these grafts were no more than acellular non-vital films of connective and elastic fibres. To what, then, can be ascribed the successful results so often reported, successful in so far as stubborn indolent ulcers were healed with sound epithelium ? It is impossible to be certain. The most likely reason is that the application of the grafts and their temporary " t a k e " cut down the magnitude of the raw area, and mitigated the infection and allowed marginal epithelial growth to proceed. No doubt, too, the little extra care in dressings and cleanliness that was accorded to the reputedly delicate grafts helped. The tantalising thought persists, however, that zoografts might have, as so many of their users thought, a specific stimulant effect on the growth of epithelial cells. To-day it would be quite unjustifiable to use living animal tissues as grafts in man ; nor is it probable that they will ever be so used again. It is none the less fascinating to speculate on the possible developments of zoografting had it been successful. Although satyrs, centaurs, and mermaids might have remained mythological figures, human chimmra," of an equally repulsive character would certainly have been produced. Perhaps there is something to be said for the attitude of the Russian divines who considered the first zoograft so immoral an act as to warrant excommunication. It is a pleasure to record my thanks to M r Terry, the librarian, and Dr A. L. Goodall, the honorary librarian, of the Royal Faculty of Physicians and Surgeons of Glasgow, for their help in tracing references, and to Mr IV. Tod Ritchie for his assistance with the Latin translations.

REFERENCES ALDRICH,N. B. (1893). Boston reed. Surg. J., 128, 336. ALLEN,W. (~884). Lancet, 2, 875. ALTRAMIRANO,F. (I880). See annotation, Lancet, i, 994. AMUEK'REN,JOBUS(I682). " Observationes Medico-Chirurgic~eex Belgico ab A. Blasio." 8re. Amstel. BERT,P. (I863). " De la greffe animale 4°." Paris. BRADFORD(I887). Annotation in Brit. med. J., 1887, I, IO63. CHEYNE,W. W. (r89o). Practitioner, 44, 4oi. CozE (1872). C.R. Acad. Sci., Paris, 74, 642. DUSOUSqUET-LABOR~ERIE(1886). Gaz. H6p Paris, 59, iI71. DUtC~mL(I89O). Referred to by Paris correspondent. Brit. reed. J., 2, 112. FILLETDE GRANDMONT(1890). Reported in Med. Pr., 2, I66. 3E

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FOWLER, G. R. (1889). Ann. Surg., 9, 179GIBSON, T., and MEDAWAR,P. B. (1943). J. Anat., 77, 299LEE, E. W. (188o). Boston med. surg. J., io3, 260 and 355. McGILL, A. F. (1889). Lancet, 2, 848. MASTERMAN, G. F. C. (1888). Brit. med. J., x, 187. MILES, A. (1889). Trans. med.-chir. Soc. Edinb., 9, 33. -(1895). Edinb. Hosp. Rep., 3, 647. PETERSEN, O. (1886). Annotation in Lancet (I886), i, 8Ol. PEYROT (1886-87). ft. Mdd. Paris. Quoted by Brit. reed. J., 1887, I, 352. POLLOCK (1870). Brit. reed. J., 2, 565 . RANKING, G. (19o6). Lancet, 2, 13o4 . RAVEN, T. F. (1887). Brit. med. J., 2, 623. REDARD, P. (1888). Un. todd. Paris, 45, 3Ol. Abstracted in Brit. med. J. (I888), 2, lO18. REVERDIN, J. L. (1869). Bull. Soc. Chir. Paris, 187 o, 2 S6r., IO, 511. -(1871). C.R. Acad. Sci., Paris, 73, 128o. SI~DILLOT, CH. (I868). " Contributions ~ la Chirurgerie," vol. 2, p. 589. Paris. SMITH, G. S. (1895). Boston reed. surg. ft., 132 , 179. VAN METER, M. E. (189o). Ann. Surg., 12, 136. VORONOFE, S. (1925). " Rejuvenation by Grafting." London : Allen & Unwin.