TRANSPLANTATION OF VASCULARIZED COMPOSITE ALLOGRAFTS. REVIEW OF CURRENT KNOWLEDGE

INTRODUCTION

Transplantation of composite tissues as a surgical option in plastic surgery is a logical step in the reconstructive ladder. This is an allogeneic transplantation, i.e. transfer of tissues from one person to another person of the same kind. This technique, although it seems modern, had been used in the past and it has been described for the first time in a collection of bibliographies of saints called Legenda Aurea, which dates back to 1260, an the author was an Italian Dominican monk Jacob de Voragine. The event was supposed to happen 348 years after Christ. In one of the legends, Saint Kosmas and Saint Damian amputated a limb to a Christian sexton and replaced it with a limb from a dead Ethiopian person. It is difficult to assume that this event really happened, but it is obvious that the option to replace diseased or missing parts of the body with the same part from another individual has been an idea of people many centuries ago.

Gaspare Tagliacozzi, an Italian surgeon from the 16^th century, describes clinical allogeneous transplantation in his book “De curtorum chirurgia per insitionem”. Skin flap from the forearm of a slave was used for reconstruction of the nose of a healthy patient. The flap was not taken and Tagliacozzi concludes that allotransplantation is technically possible, but there are some practical obstacles to connect the tissues of two different individuals for sufficiently long period of time.

The name “Composite Tissue Transplantation – CTT” was developed at the beginning of experiments with transplantation of the limbs in order to differentiate it from organ transplantations and to emphasize that transplanted part of the body consists of various types of tissues, such as bones, tendons, ligaments, muscles, nerves, vessels, fat, skin, etc. The name is still used, although at the time in case of transplantations of the joints, larynx and other tissues, it looses relevance and the opponents also emphasize that even transplanted organs contain connective tissue, vessels and nerves. Currently the name CTT has often been replaced by the term Vascularized Composite Allotransplant – VCA, which more precisely defines that it is an allotransplantation of a composite block of tissues.

LEGAL ASPECTS AND REGISTERS

Transplantation of composite tissues has been performed in several countries in the whole world. It is not possible to find the exact number of these procedures, although there is an international register. This is because there is no legal obligation to register these procedures and therefore data in the register are not exact and complete; moreover data from some countries were removed due to inaccuracy and inconsistency^1,2. There was also the International Hand and Composite Tissue Allotransplantation Society established, which organizes regular congresses. The last congress took place in April 2015 in Philadelphia.

In the United States were the requests for these procedures registered at the United Network for Organ Sharing (UNOS) under the name VCA in July 2014. This official status and registration was necessary because from February 2014 there were 28 of these operations performed at 11 sites and another 9 patients in 6 sites waited for this procedure. In the memorandum of UNOS there were nine criteria established, which must be fulfilled for the tissue to be registered as VCA in the register:

1. tissue is vascularized and requires surgical connection of vessels, to be functional
2. contains many types of tissues
3. is harvested from a human donor as an anatomical/structural unit
4. is transplanted to a human recipient as an anatomical/structural unit
5. there is minimal manipulation (without processing)
6. it is used for homologous replacement (same function in recipient as in the donor)
7. it is not combined with another artificial device
8. it is sensitive to ischemia and therefore may be stored only for temporary, short period of time
9. it is sensitive to rejection and requires immunosuppressive therapy³.

In every country transplantation of composite tissues must respect regulations of that particular country. Every workplace, where these procedures are performed, submits an application for approval at a responsible ethics committee and there are detailed informed consents prepared for the procedure focusing on the risks and adverse effects of immunosuppressive therapy.

When planning transplantations, it is necessary to think also of other possible legal consequences (mainly during transplantation of the face and hands) such as identification of individuals, fingerprints, etc. Mainly fingerprint is currently an identification criterion extensively used in criminology, but in some countries it is a part of passports, they are used for access to a mobile phone, to an employment facility, to protected areas, etc. Even the social aspects of the procedure should not be omitted. In Italy, e.g. after transplantation of a hand, was a disability pension removed from a patient.⁴

PSYCHOLOGICAL ASPECTS

Very important component of patient preparation is good psychological and psychiatric examination. Based on entry examination were e.g. in Italy selected only four suitable candidates for hand transplant out of 400⁴ and in the United States in Louisville there were 9 candidates selected from 213 patients. Mainly in transplantations, which significantly influence the body scheme, such as hand and face transplant, are the psychological questions very important⁵. Psychological and psychiatric examination focuses mainly on issues from social history, support of the environment, general compliance with therapy, ability to make decisions, emotional and cognitive capabilities and characteristics of the recipient. Other recommended psychological examinations and preparation should focus on body image adaptation, on the ability to cope with the change of body image, on the extent of adaptation after hand amputation or facial mutilation, on accepting prostheses and epitheses, on phantom phenomenons. Finally, it is very important to properly evaluate the patient with regards to realistic expectations of the result of transplantation and in certain way also regarding the ability of the patient to accept that this therapy is still sort of clinical research and it is not possible to certainly estimate short and long-term results^6,7.

In these transplants, mainly in case of transplantation of the face and hands, it is important to know that there will be significantly higher mental pressure on the patients than on the recipients of organ transplants. There are several factors why. First, the recipient must adapt to the situation that the transplanted organ – organ from a dead person – will be visible for him/her but also for the environment, family and friends. Furthermore, the transplanted organ starts to function spontaneously and immediately, if transplantation was successful. In case of reconstructive transplantations is necessary long term and tiring rehabilitation for restoration of function and that is happening during the period of most intensive and demanding immunosuppression. These transplantations are moreover exceptional and it is necessary to consider also a great interest and pressure of media.

The most significant evidence of failed psychological preparation and examination before transplantation is the first successful transplantation of the hand in 1998, which actually started further progress. The recipient of a transplanted hand, Clint Hallam, stopped cooperating with the medical team four months after transplantation, stopped with rehabilitation and administration of immunosuppressive therapy. The limb had to be amputated two and a half years after the transplantation. Another example of failed psychological preparation is the need for reamputation of a transplanted penis in a recipient in China less than two weeks after transplantation⁸.

ETHICAL ASPECTS

Transplantation in reconstructive surgery may be justified only when there are three basic conditions fulfilled. There must be a real need to perform these procedures, it must be sure that we achieve a good functional and aesthetic result with the procedure and finally the benefit of the procedure should outweigh its risks. The first condition is certainly fulfilled. There are real patients who need transplantation. Their defects mean a great physical, psychical and social burden for them and the condition cannot be solved in any other way. Achievement of good functional and aesthetic results has been shown in an experiment, but also by the experiences from clinical reconstructive surgery. Trials on animals demonstrated almost full function of the transplanted limb. The function of the limb after transplantation achieves in average 50–70% of function of the healthy limb and the aesthetic results are better than in case of prosthesis. Whether the benefit outweighs the risks is perhaps the most difficult question to answer, because it is not possible to objectively evaluate the extent of suffering and the improvement of quality of life. Similarly to all allogeneous transplantations also in reconstructive transplantations is needed life-long immunosuppressive therapy with its risks and adverse effects. And this is the most controversial point of reconstructive transplantations. Experts and lay public have been divided into two groups, to the advocates and to the opponents of the method. The basic arguments of the opponents focus on adverse effects of immunosuppression due to the actual toxicity of the drugs, possibility of opportunistic infections and development of malignancies.

Transplantation in reconstructive surgery differs extensively from organ transplants. There are healthy individuals in good physical and mental condition chosen for the procedure. These individuals have no serious disease, which would significantly reduce their functional capacity and it is possible to expect better results and lower risk of adverse effects^9–11. Questionnaire research performed in Great Britain between lay public demonstrated that only 10% of respondents were principally against the idea of reconstructive transplantation. Another research performed in the United States confirmed that people were willing to accept a higher risk in case of facial transplantation; up to 87% of healthy people would undergo facial transplantation even with 50% risk of rejection within one year¹². These results demonstrate that lay public considers reconstructive transplantation to be useful. Research was performed also within the expert community. Among the specialists in hand surgery, there were only 13% who strongly agreed in case of a suitable indication and 7% strongly disagreed. Similar research among American plastic surgeons and specialists in burn surgery regarding transplantation of the face demonstrated that 26% of specialists consider facial transplantation to be ethically acceptable, but 6% refuses it principally regardless of the conditions^13,14.

The relationship of expert and lay public to reconstructive transplantations developed naturally. While before 2002 no publication approved facial transplantation, after 2008 almost all publications considered this procedure to be ethically justified for severe disfiguration¹⁵.

SPECIFICATION OF DONOR SELECTION

A logical specific feature during the selection of a donor for transplantation of visible parts of the body – hand, face, abdominal wall, lower limb, etc. is that apart from immune system concordance, it is also necessary to consider aesthetic and functional concordance. It is therefore necessary to consider skin colour, race in general (mainly typical race differences on the face), character and colour of hair. Weight of the donor and recipient must also be similar; the size of the limb depends on weight and even the difference in type and extent of musculature may be surprising. Very important is also the age concordance; hand and face of an old person look completely different than in a young person. These additional selection parameters of course make the selection very difficult and limit the potential range of donors.

IMMUNOLOGICAL ASPECTS AND IMMUNOSUPPRESIVE THERAPY

Allogeneous transplantation naturally requires immunosuppressive therapy to prevent rejection. Reconstructive transplantations are not performed from vital indication but to improve quality of life of the patients. This provides benefit, but also main ethical dilemmas of these procedures. The advantage is that it is possible to select patients for these transplantations who are generally healthy and in good condition compared with patients who are in final stage of their severe cardiovascular, respiratory or metabolic disease, as in case of organ transplants. This is a clear advantage for management of complications of surgical and also other therapy, including immunosuppressive therapy. Ethics dilemma is obvious and it consists of the risk to develop malignant disease, opportunistic infections, and direct organ toxicity of drugs or metabolic changes due to the use of immunosuppressive therapy.

Immunosuppressive therapy underwent development from whole body irradiation and irradiation of transplanted organs, to the use of high doses of corticosteroids and polyclonal antilymphocytic antibodies, up to the current modern and less risky drugs¹⁶.

Immunosuppressive regimen during CTT is not standardized for the whole body, it is not unified. It naturally depends on the customs and established algorithms of each transplantation centre, as it is in case of organ transplants. Most centres perform initial therapy with monoclonal antilymphocytic antibodies with dual combination or triple combination of immunosuppressants. Doses of immunosuppressive drugs are gradually decreased to a titrated minimum when the dose is the lowest and there is no rejection. In case of an episode of acute rejection are the doses of immunosuppressants increased in general or there is a separated bolus administration of glucocorticoids initiated and it is proceeds according to the reaction. There are also ointments with corticoids or immunosuppressive active ingredients used for skin signs of rejection.

Glucocorticoids still remain the main component of immunosuppressive therapy. Mechanism of action is variable and it has been studied extensively. In the initial phase of immunosuppression are administered higher doses (dose dependent effect) of a potent glucocorticoid, e.g. methylprednisone - decline of production of several important cytokines of inflammatory reaction occurs, which include interleukins that interfere with recognition of antigens. They also have a lymphotoxic effect. Toxic effects of glucocorticoids (myopathy, osteoporosis, diabetes) significantly decline by rapid reduction of doses, therefore it is attempted to reduce the doses to a minimal maintenance dose within three months. Glucocorticoids have also a dominant effect during the management of acute rejection^16,17.

The main advantage of monoclonal antibodies compared with polyclonal antibodies is that there is reduced occurrence of adverse and toxic effects while being homogeneous and monospecific.

These antibodies are targeted specifically against alpha chain of interleukin 2, which is selectively exprimated on activated T lymphocytes. Most frequently are used daclizumab and basiliximad. These antibodies are used for limited time at the beginning of immunosuppression and they have a minimum of adverse or toxic effects.

Azathioprine and mycophenolate mofetil are used from the group of antimetabolites. These drugs are especially suitable for chronic immunosuppressive therapy, because they influence B-lymphocytes and precursor cells in bone marrow. The most important toxic effect of both drugs is suppression of bone marrow and increased risk of malignancies. While azathioprine has higher toxicity to bone marrow, mycophenolate mofetil has more pronounced effect on gastrointestinal tract. Most units prefer mycophenolate mofetil, because it is clearly more effective in the first three years of immunosuppression¹⁸.

Calcineurin inhibitors interfere with calcium dependent cascade of T lymphocytes, inactivate it and thereby prevent gene transcription of interleukin 2¹⁹. They are very effective immunosuppressants, and it has been reported in general that immunosuppressive regimens without calcineurine inhibitors are less effective¹⁶. Their use requires regular monitoring of blood, because there are very important intra-individual and inter-individual variations in their absorption and excretion. Cyclosporine has been used from 1984 and it is the first drug, which enabled successful long-term use of CTA in an animal model^20–23. Tacrolimus is a potent alternative to cyclosporine; it is 10–100x more effective in vitro. It also has a stronger stimulation effect on proliferation of hepatocytes and it has a positive effect on growth of nerves, which is important from the point of functional reconstructive transplantations. Both drugs are nephrotoxic; cyclosporine causes hypertension, hirsutism and gingival hyperplasia; tacrolimus is more neurotoxic, but only in high doses.

Sirolimus is a TOR (Target Of Rapamycin) inhibitor; it interferes with signal pathway of interleukin 2, but with another mechanism; it reduces production of immunoglobulins²⁴. It has very synergistic effect with calcineurin inhibitors and its addition to immunosuppressive regimen significantly reduces nephrotoxicity of calcineurin inhibitors. Its adverse effects include hyperlipidaemia and sometimes thrombocytopenia¹⁶.

IMMUNOLOGICAL SPECIFICATIONS OF TRANSPLANTATION OF COMPOSITE TISSUES

In comparison with organ transplantations, where the transplanted organ is consisting mainly of homogeneous parenchymatous tissue, transplants in reconstructive surgery mostly contain a complex organ, consisting of several and various types of tissues. The spectrum is wide mainly in case of hand and face transplantations. There are skin (epidermis and dermis), subcutaneous tissue, fascia, muscles, tendons, nerves, vessels, periosteum, bones, cartilage, synovium, bone marrow, and lymph nodes; in the face there is also mucosa and salivary glands. Already from the middle of the last century, it has been known that not all tissues are immunogenic the same way, i.e. they are not sensitive the same to rejection reaction of the recipient. These tissues are variably antigenic and also undergo rejection by a different mechanism. For example, muscle causes mainly cellular reaction, sometimes even stronger than skin, while skin causes generally stronger mixed, cellular and humoral immune reaction^25,26. Generally, the most immunogenic tissue is skin, mainly epidermis and then mucosa. It is logical, because skin and also mucosa create primary barrier and protection against foreign antigens and they are very rich of professional competent immune cells.

Some kind of rejection ladder was established, which indicates the willingness of individual tissues for rejection reaction. If we consider systemic rejection (cellular and humoral), then skin is followed by subcutaneous tissue, bone, and muscle and least immunogenic are vessels, tendons, cartilage and nerves. An interesting finding was that a transplanted limb as a whole induces milder rejection reaction then individual tissues (muscles, skin, etc.) transplanted separately ²⁵.

Sensitivity of skin and mucosa to acute rejection in the recipient is of course a great disadvantage during transplantations, because it requires higher doses of immunosuppressive drugs and it is a risk factor of failure of the whole transplantation. On the other hand, it is positive, because skin is an organ available for visual examination and signs of acute rejection (redness, swelling, papulous exanthema) can be detected very quickly without having to perform biopsy or special laboratory tests. It is then possible to initiate early and swift treatment, before other tissues are affected by rejection.

Differences in immunogenicity of individual tissues are manifested also by a phenomenon called split tolerance. This phenomenon and name was described in 1959 by Billingham and Brendt and it is a situation when one tissue from the donor is tolerated by the recipient, while the other is rejected²⁷. Mathes in an experiment describes split tolerance in one organ - transplanted limb - where epidermis was rejected, while other tissues including dermis remained without signs of acute rejection only with stable mild lymphocytic infiltration²⁸. Split tolerance was then confirmed also in the first patient with a transplanted hand, who stopped using immunosuppressive therapy four months after the procedure and in a sample of patients from Innsbruck and China²⁹. Histological examination of the hand, which was subsequently reamputated two and half year after transplantation, demonstrated that signs of rejection were present only in skin, not in other tissues.

CLINICAL RECONSTRUCTIVE TRANSPLANTATIONS

Hand transplantation

The first, most common and probably also most known transplantation in reconstructive surgery is hand transplantation. Historically the first allogeneic transplantation of the hand was performed already in February 1964 in a 28-year-old sailor in Ecuador. In spite of therapy with corticoids, 6-mercaptopurin and irradiation, the hand had to be amputated two weeks after the procedure due to rejection³⁰. The first successful operation with long-term survival of the transplanted hand was performed in 1998 in Lyon, France by a mixed team from France, Australia and Italy (Doubernard, Owen and Lanzetta). The patient stopped cooperating although the procedure was successful, the graft was taken well and the function of the limb was favourable. Since Day 120 after transplantation he stopped using immunosuppressive therapy and stopped rehabilitation and the hand was reamputated 861 days after the procedure. The first bilateral hand transplant was performed also in Lyon by the same team in 2000. So far there were approximately 30 unilateral, 25 bilateral hand transplants and 2 times even transplantation of the fingers performed². Transplantation of fingers was performed in China. Reconstructive transplantation in a child was performed – according to available sources – only in one case until now and this was hand transplantation. It was a bilateral transplantation in an eight-year-old boy, who lost all four limbs due to infection at the age of two years. The patient already underwent kidney transplant and immunosuppressive therapy. The procedure was performed in July 2015, the graft took well and early results were favorable³¹.

After transplantation of course follows long-term intensive rehabilitation and it has been reported that transplanted hand reaches approx. 50% of the function of a healthy hand. The patients reported improvement of quality of life approx. by 75%; all patients after operation are able to care for themselves, most of them are able to perform their original occupation, hobbies and interests. To facilitate rehabilitation there were special aids and devices developed such as sensory glove of professor Lundborg, which takes the advantage of the capacity of human brain for multimodal plasticity³². The problem of chronic rejection and loss of function was not yet clarified, however, in the first patient, who stopped using immunosuppressive therapy and the hand was reamputatted, was found that from all the tissues only skin underwent rejection. This finding is a great promise that even after a long time the limb can remain functional. According to the available sources it has been necessary to perform six reamputations of the limb worldwide and seven in China due to various complications.

Transplantation of the face

The second most popular transplantation of composite tissue is undoubtedly facial transplantation. The procedure is more demanding than in case of the hand and mainly the lack of success of the procedure has catastrophic consequences for the recipient. The first face transplantation was performed also in France in 2005. So far, there were approx. 35 facial transplants performed, 19x parts of the face, 16x the whole face³³. Indications for the procedure are modified in various sites, however in general these patients are 18–60 years old, the defect of the face must be greater than 25% or it must affect dominant aesthetic and functional units such as the nose, lips, eyelids. Transplantation of the face is not useful to restore natural appearance of the face; it is used to restore function such as breathing, intake of food, taste, smell, speech and facial mimics and sensitivity. Great number of patients requiring facial transplantation suffers from loss of smell and has a tracheostoma due to obstruction of upper airways or gastrostoma due to inability to swallow food.

From the technical point of view is facial transplantation actually a transfer of (osteo)-myocutaneous free flap with the need to suture vessels and sensitive and motoric nerves. Before the procedure, it is necessary to perform detailed examination of the skeleton to visualize the actual defect and also function of the joints, tongue etc. It is also very important to examine thoroughly the recipient’s vessels on the neck, because many vessels were injured or destructed by the actual trauma or resection of a tumour or were used already in the previous reconstructive procedures. The studies have shown that for revascularization of the whole face, it is enough to perform a suture of the facial vessels even in case that larger bone segments were harvested provided the harvest of the face is correctly performed with preservation of collateral vascular network. More advantageous is however performance of anastomosis in several vessels. Reconstruction of all available nerves must be performed the same way in order to achieve optimal motoric and sensory functions^33–37. Reinervation of transplanted face occurs in approximately 18 months and from the day 10 there is a possibility to speak and eat. According to the current results, breathing recovers in 93% of patients, speech in 71% and mimics also in 71% of patients³⁸.

Complications in facial transplantation may be surgical, most frequently thrombosis of microsurgical anastomoses; most complications or adverse events are due to immunological reasons and use of immunosuppressants. Acute rejection occurred in 80% of patients; events were treated well. The worst, catastrophic scenario, i.e. superacute rejection with a loss of the transplant, did not occur yet. Chronic rejection was reported so far only once and manifested by restriction of function – opening of mouth and atrophy of mucosa³⁹.

There were also serious complications reported in facial transplantation. In a patient with a combined facial transplantation and both hands was required reamputation of the hands. There were five deaths after facial transplantation reported. The cause was lack of cooperation of the patient, suicide, recurrence of carcinoma, sepsis and lymphoma with breathing difficulties^40,41.

One of the greatest specific problems of facial transplantation is currently very short time of tolerable ischemia that is only 4 hours, which significantly restricts the geographic radius of possible donors. To prolong ischemia time it is possible to consider extracorporeal perfusion that is sometimes used in transplantation of solid organs. There is also very limited number of donors and the waiting time for facial transplantation in the United States is now approximately 180 months.

Transplantation of scalp

Transplantation of scalp was performed already in 1981 in the USA between identical adult twins-sisters. Immunosuppressive therapy was not used. The procedure was successful, complete take occurred, allo-transplantate healed without signs of rejection and from the fifth day after the procedure started growth of hair⁴².

Chinese authors performed transplantation of a half of the scalp, both ears and skin of the nape in 2003 in a 72-year-old patient with extensive malignant melanoma. Male scalp was used for transplantation, not a female scalp. The defect developed after a resection of a tumour and reconstruction with transplantation was performed together with radical resection of the tumour. According to the classification of the tumour was the survival of the patient approx. 25% in 5 years. The procedure was successful; 120 days after the operation was the patient compensated, allotransplant was taken without complications. There is no more information about the fate of the patient⁴³. There was rather critical discussion against the use of allotransplantation, against this technique and usage of a male donor etc. in this particular patient⁴⁴. In 2015, the team of doctors in Houston, Texas performed combined transplantation of kidneys, pancreas and calva with a scalp. This was a patient who had transplanted kidneys and pancreas and these organs were failing. In the area of the hair bearing part of the head was performed repeated resection of a leiomyosarcoma, which resulted in an extensive defect of scalp and calva. During a fifteen-hour operation was performed complex transplantation of failing organs and part of the skull with a scalp from the same donor⁴⁵. The procedure was successful and all transplanted tissues healed.

Transplantation of the larynx

Loss of the larynx with a tracheostoma is associated with deteriorated taste or even loss of taste and smell; there is higher incidence of upper airways infection, but mainly there is loss of voice. The affected individual is stigmatized in personal and social life, which is also documented by the research performed in patients after laryngectomy in the USA, where 75% of patients after explanation of the procedure, of the risks etc. would undergo transplantation of the larynx⁴⁶.

The most immunogenic tissue in the larynx is mucosa; cartilages are minimally immunogenic. Tolerated time of cold ischemia of the larynx was experimentally demonstrated to be 20 hours, which is very favourable for the management of these transplantations. For adequate perfusion of the larynx should be sufficient anastomosis of unilateral superior thyroid artery and its first branch, the superior laryngeal artery; more convenient is of course performance of bilateral anastomoses⁴⁷. Greater problem is however innervation of the larynx, which is necessary for good function and therefore for the success of the procedure - restored speech, regulation of breathing, swallowing, coughing reflex, etc. For complete re-inervation of the larynx, it is necessary to perform suture of the superior laryngeal nerve and recurrent nerve bilaterally^48–51.

The first clinical transplantation of the larynx was performed in 1969 in a patient after resection of the larynx for carcinoma. The procedure was successful, the graft was taken well and the function was restored, however 7 months after the procedure there was recurrence of a tumour and the patient died⁵². Another transplantation was performed in 1998 in the United States of America in Cleveland Clinic Foundation in case of a post-traumatic loss of the larynx with healing and restoration of function ^53,54 and in Meddeline in Columbia in South America, where there were 13 of these procedures performed and the success rate was 90%⁵⁵. Farwell from California describes another case report of larynx transplantation with a part of trachea in 2013 and it was successful⁵⁶.

Transplantation of the larynx is a very attractive procedure (it is estimated that in the world there are approx. 140 thousand patients after laryngectomy each year), but currently it is used very little since most of the patients loose larynx due to a malignant disease and immunosuppressive therapy in these patients is very discutable⁵⁷.

Transplantation of trachea

Trachea is an anatomical connection between larynx and bronchi; its function is therefore more complex – ventilation, voice, and it ensures balance of respiratory secretion. For the patency of trachea, it is necessary that it is solid in transverse direction, but elastic in longitudinal direction. This is enabled by special anatomic construction with cartilage rings connected by ligaments. The defect of trachea shorter than five centimetres may be treated with mobilisation and suture; longer defects are difficult to treat. The greatest problem of tracheal transplantation is its vascularization, which is not provided by larger vessels, but by several small segmental vessels, which are difficult to anastomose. Trachea is therefore usually transplanted individually as a non-vascularized graft, which is transplanted to a heterotopic well-perfused bed and it is transferred together to the neck or the transfer is performed only after complete take of the graft and vascularisation is restored in a second stage.

The first transplantation was performed in 1979 in two stages. For the heterotopic bed was used sternocleidomastoid muscle⁵⁸. In 1993, Levashov described single stage transfer of non-vascularized trachea wrapped into omentum; stenosis with the need to insert a permanent stent however occurred⁵⁹. In 31 paediatric patients was performed orthotopic transplantation of cryopreserved trachea with a success rate of 85%^60,61. In Austria was transplanted trachea to one patient into the distal omentum, however it was not used finally, because the trachea of the patient could be reconstructed with a suture after extensive mobilisation⁶². Systematically was tracheal transplantation investigated in Belgium, where two-stage heterotopic transplantation with transfer via the forearm was performed in 2005 in five patients. After healing was trachea transplanted to the neck on radial vessels⁶³.

The only transfer of vascularized trachea together with the thyroid gland with vascularization using the inferior thyroid artery was performed in Colombia by Tintinago in 2003; repeatedly was also performed transplantation of larynx together with a part of trachea using the same technique⁶⁴.

Transplantation of the tongue

The tongue has a function in personal and social life; patients without tongue have difficulty speaking and speech is incomprehensible; they have problems with swallowing, they don’t have taste and the tactile function is also missing. The tongue has an important function also for oral hygiene and chewing of food. Loss of tongue is usually caused by an oncological disease, only sometimes is the cause traumatic or other.

Transplantation of the tongue was performed in 2003 in Austria in a patient after resection of a tongue due to a carcinoma. Reconstructive procedure was performed together with the resection procedure after chemoradiotherapy due to advanced tongue carcinoma. Taste and swallowing restored; however, the patient died due to generalization of the original tumour. There is again a consideration about the suitability of transplantation with immunosuppression in oncological patients, however the authors, who performed the procedure state that according to studies there is no higher occurrence of carcinomas of the head an neck in patients with immunosuppression⁶⁵. Another transplantation of the tongue was performed in 2013 as a composite transplantation together with the whole face and upper and lower jaw. This was so far the most complex transplantation in the facial area. The face of the patient was devastated after high-energy ballistic injury to the central part of the face^66,67.

Neck transplantation

Transplantation of the neck was performed in a patient in 2015 in Poland. The recipient was a patient, who previously underwent kidney transplantation many years ago. In 2009 was removed an extensive tumour of the larynx. Since the patient had no recurrence for the last 5 years, and he had immunosuppressive therapy after kidney transplant, there was complex transplantation of cervical organs – larynx, trachea, upper part of the oesophagus, thyroid gland and parathyroid glands, hyoid bones, muscles of the neck and skin island performed^68,69.

Transplantation of the abdominal wall

Abdominal wall serves apart from others for the locomotor and postural function and as an important cover of the intra-abdominal organs. Its devastation may occur by injury, tumour, but also due to recurrent surgeries with multiple scars, stomas, etc. Its covering function is dominant, mainly in case transplantation of intra-abdominal organs, such as stomach, bowel, liver, pancreas, kidneys and others are needed. Transplantation of the abdominal wall was so far performed always as a combined procedure with multivisceral transplantation. This naturally removes the ethical problem, since its performance is vitally important and immunosuppressive therapy is not used due to transplantation of the abdominal wall only, but also due to the intra-abdominal organs.

Transplantation of the abdominal wall was performed in the USA in nine patients, first in 2001⁷⁰. Abdominal wall was harvested on iliac vessels. Iliac vessels and also intra-abdominal vessels – aorta and inferior caval vein – in the recipient were used for anastomosis. They were performed with a macroscopic technique. Most transplantations of the abdominal wall were performed from an identical donor, from whom were harvested the organs; it was twice performed as delayed procedure from another donor. In 2007, Cipriani from Bologna reported experiences of three patients where microsurgical technique with an anastomosis of the inferior deep epigastric vessels was used⁷¹. Authors from Great Britain performed transplantation of the abdominal wall in six patients, where the long time of ischemia of the abdominal wall was bypassed by temporary heterotopic revascularisation on the forearm vessels. After termination of visceral transplantation was abdominal wall disconnected from the forearm and orthotopic revascularisation was performed⁷².

There is also a report about transplantation of a split abdominal wall, i.e. transplantation of deep abdominal fascia only. This method requires separated suture of vessels, since visceral fascia is sufficiently perfused by the vessels in ligamentum falciforme connecting with the liver. This technique was used in three paediatric patients^73,74.

Survival of patients after transplantation of the abdominal wall is relatively low. Selvagi summarizes the results of a team from USA and Italy⁷⁵. Only five of 14 patients survived eight years after the procedure. It was important that not even one of the patients died due to direct complications of the abdominal wall transplantation; the cause of death were complications of visceral transplantation, sepsis or lymphoproliferative disease.

Transplantation of skeleton

Extensive devastation of weight bearing bones and joints in association with destruction of ligamentous and tendineous apparatus is a great reconstruction problem and it is often impossible to use standard techniques such as microsurgical transfer, segmental transport, distraction or prosthetic joints. Another option is amputation and prosthesis or joint fusion of the knee joint with shortening of the limb and subsequent distraction. Even here there is a possibility of allogeneous transplantation. For more than 50 years have been used allogeneous bone grafts for smaller bone defects, usually treated with cryopreservation. It is estimated that in the USA there were approximately on million of these grafts used in 2013.

Already in 1902 was performed allogeneous transplantation of a non-vascularized half of a joint in three patients⁷⁶. Lexer performed 23 transplantations of non-vascularized joints including the knee between 1907 and 1925. In spite of significant radiological degenerative changes was the function of the joints good and painless⁷⁷. In 1970, Volkov described reconstruction of a part or whole joint in 150 patients. Joints were not vascularized⁷⁸. In patients with a transfer of small joints or small parts of joints were the results favourable; in big joints, however, were the results very unsatisfactory, basically none of the patients experienced good take and function.

The first vascularized transfer of femoral diaphysis was performed in 1990 in France with a good result. Doi reported family allotransplantation in 1994 between the mother and son with complicated healing and need of reoperations, but with a good result at the end⁷⁹.

A German team investigated this topic more systematically and performed three transplantations of a long segment of femoral diaphysis and six transplantations of the knee joint between 1995 and 2003⁸⁰. The results were not favourable; healing was complicated with the need of reoperation and with the use of autogenous cancellous bone grafts. In case of the knee joints, one of six patients healed well with favourable function. Other joints had to be removed due to rejection, infection or lack of cooperation of the patients and below knee amputation or fusion of the knee joint was needed⁸¹.

Transplantation of the lower limb

Transplantation of the lower limb has been refused for a long time due to two reasons. The first is that lower limb is predominantly a locomotor organ and it is very well replaceable by a prosthesis or a wheel chair. The second reason suggests that it is difficult to expect good functional results with regards to the length of the nerves, which are needed for regeneration. For correct function of the lower limbs - gait, standing, balance, stability, etc., it is necessary to achieve good reinervation of the limb in terms of motoric and also sensitive innervation, mainly in the area of the sole.

In 2012 was performed the first transplantation of both lower limbs at the thigh level. The patient was a 22-year-old young man, who lost lower limbs in a car accident. The patient was not able to walk with prostheses, refused osteointegrated prostheses and moved only on a disability wheelchair. Transplantation was successful and one year after the operation was the patient able to perform extension in the knee and plantar flexion of the foot; Tinnel sign was present at the level of the ankles⁸². Further improvement of the limb function is expected.

Penis transplantation

Penis is one of the dominants of male gender and its loss is associated with several functional, mental and social problems. The patient cannot urinate in standing position, he is unable to have sexual intercourse and fertilize the partner. The loss of penis is possible by a trauma, resection for a tumour and a large group is a result of complications of unprofessional circumcision, mainly in African countries, where the presence of penis is required for full social life of males.

Transplantation of penis was performed for the first time at the Military general hospital Guanzhou in China in 2006 in a 21-year-old male with traumatic loss of the penis. From the tenth day after the operation was the patient able to urinate; due to psychological complaints of the patient and mainly of the wife had the penis be reamputated two weeks after the operation^83,84. Second successful transplantation was performed in South Africa in 2014. The patient lost penis after complications of circumcision at the age of 18, when he already had active sexual life. According to the reports from press was the patient able to urinate, had erection, orgasm and ejaculation five months after the operation^85,86.

Transplantation of uterus

Transplantation of uterus is for now the only one from the reconstructive transplantations, which may be really planed only for a temporary period of time and after successful pregnancy and labour may be removed and immunosuppressive therapy stopped. This procedure is intended for young healthy women, who lost the uterus for some reason or their uterus is not functional, they are still in childbearing age and they wish to have own children. Transplantation of uterus is currently the only possible therapy of uterine infertility. Experience in young women using immunosuppressive therapy after organ transplantation demonstrate that they can successfully complete pregnancy of a healthy child⁸⁷ and in an experiment in sheep and rats was achieved complete pregnancy after uterine transplantation^88,89. Therefore the concept of uterine transplantation to achieve pregnancy and carrying of children to term is real.

Uterus transplantation in humans was performed for the first time in Saudi Arabia in 2000. Uterus was taken well and normal menstruation bleeding occurred for 3 times. However, thrombosis of vessels and necrosis of uterus occurred after three months and uterus was removed. Another transplantation of uterus was performed in Turkey in a woman with Rokitansky-Kuster-Hauser syndrome; the uterus was taken well and regular menstruation cycle occurred. After a second embryotransfer the patient got pregnant, but in the sixth gestation week the foetus died⁹⁰. The team of doctors from Sahlgrenska University in Gothenberg in Sweden performed a series of nine uterus transplantations between 2012–2013 in women with absolute uterine factor of infertility. In 2015 was published an article about successful full term foetus after artificial fertilization in one of these women. The patient was 35 years old and the donor of uterus was a living woman aged 61 years. In vitro fertilisation in the patient and her partner was performed before transplantation of uterus and harvested embryos were cryopreserved. One year after transplantation was one embryo transferred to the uterus and pregnancy occurred. The patient was admitted in the 32^nd week due to preeclampsia and due to pathological cardiotocography record of the foetus was performed delivery with Caesarean section. Vital healthy foetus of male gender with birth weight of 1770 grams and length of 40 cm was born and only phototherapy was required. The mother was discharged to home care two weeks after labour; the child was thriving well and the weight was 2040 grams⁹¹.

Transplantation of skeletal muscle

Transplantation of muscle may be considered in case of a devastation injury to reconstruct function, but also only to cover defects in special cases. Separated muscle has never been used for reconstruction of muscle function. In 1998, in the USA, was however performed transplantation of skeletal muscle for reconstruction of a scalp defect in a patient after resection of extensive spinalioma. This procedure was indicated as a more gentle, because the patient was already on immunosuppressive therapy after kidney transplant. Complete healing took place without rejection ⁹².

Transplantation of tendons

Extensive loss of tendons, mainly in the area of the forearm and hand may be equivalent from the functional point to a complete loss of the limb. Autologous tissues may be used for reconstruction. However, in case of a greater loss, it may be difficult or even impossible. Tendons have very low immunogenic potential and therefore their use as allogeneous transplant is beneficial and is associated with minimal to only temporary immunosuppressive therapy.

Already in 1959 was performed transplantation of non-vascularized flexor tendon complex containing both flexors, tendon sheath and peritenonium. Transfer of 11 tendon complexes was performed in ten patients. It was great in seven of them, the surgery failed in four of them⁹³. In general the same operation with similar results was described in two patients ⁹⁴. In 1990 in France were performed 2 transplantations of fresh vascularized tendons – tendon system supplied by ulnar artery. After temporary immunosuppressive therapy the tendons healed without signs of rejection and restoration of function occurred⁹⁵.

Tendon non-vascularized cryopreserved allotransplants are commonly used in orthopaedic surgery for reconstruction of anterior and posterior cruciate knee ligament, ligamentum patelllae, extensor system of the knee and patellar instability, etc. In this case is used Achilles tendon, ligamentum patellae, fascia lata, rotator cuff, tendon of tibalis posteroir and anterior and others⁹⁶.

Transplantation of nerves

Allotransplantation of nerves was first attempted already in 1885, however without description of the functional result⁹⁷. In the 20^th century were performed several clinical transplantations of non-vascularized nerve grafts with very contradictory and disputable results. In 1990 in the USA was performed transplantation of frozen nerve allografts in patients with massive loss of peripheral nerves with exact description of the technique, immunosuppressive therapy and results. In seven procedures, there was one rejection; in 4 out of 6 taken transplants there was partial restoration of function^98,99.

Transplantation of vessels

Venous non-vascularized allografts as an alternative for bypass in patients with lack of own vascular grafts were used by Carpenter in 1997. Patency of grafts was however poor¹⁰⁰.

Anorectal transplantation

In an experiment on animals was performed transplantation of anorectal complex^101–103. Japanese authors performed cadaveric transplantation of anorectal complex in one human with a suture of pudendal vessels and nerves and inferior mesenteric vessels. Surgery took 7 hours and the diameter of vessels and nerves was 1–2.5 mm. Authors concluded that the procedure is technically and anatomically possible in humans and it is intended for perspective patients with loss of anorectal complex as an alternative of life long colostoma¹⁰⁴.

Complex rare transplantations

As a rare transplantation may be mentioned transplantation of the left upper limb between homozygous twins in 2000 in Kuala Lumpur in Malaysia. The procedure was performed in the first month of life of the twins, when one foetus had anencephalus with severely damaged brain and unable to survive long term and the second foetus had a deformed left arm with missing hand. There was no immunosuppression administered and the graft healed well with a great functional result^105,106.

Similar procedure was performed in Canada in 2004 in two Siamese twins (non-sanguineous ischiopagus) who were not able to survive both after separation. One lower limb was transplanted from the non-perspective to a perspective twin. Healing took place without immunosuppression with satisfactory function; six years after the procedure was the limb shorter by 6.5 cm. The range of motion in the hip and knee was appropriate; there was difficult plantar and dorsal flexion of the foot^{107, 108}.

CONCLUSION

The desire and need of every individual to achieve physical completeness and perfection accompanies the whole human history and it is one of the most important human needs. Surgical methods to fulfil this desire led from reconstruction through replantation and microsurgical transfers up to allogeneous transplantations.

Reconstructive transplantation is a clinical reality. Operations have been performed in various countries in the whole world; totally there were about 180 performed. Basically all complications of immunosuppression and surgical technique occurred. Serious complications and failure occurred in approximately 21 cases. According to available data, three patients after complex transplantations – four limbs simultaneously in one case and both hands together with face in two cases died; another two died after facial transplant. Furthermore, several patients died due to indirect complications, mainly generalization of the original malignant tumour.

Most frequently is transplanted the dominant hand or both hands, followed by the face. Other transplantations are rather rare. Allogeneous transplantation after almost twenty years of uncertainty and disputes gained its place in the spectrum of procedures in reconstructive plastic surgery. It is still an exceptional procedure, performed in specialized centres and remains reserved for a very narrow group of severely disabled and highly motivated patients. The original scepticism and refusal clearly moved towards interest and acceptation, mainly based on achieved results from the actual patients who underwent the transplantation. The method is still not a routine and there remain several specific questions to be answered, mainly concerning the long-term functional results, transplantation in children or in oncological patients.

The risks of immunosuppressive therapy are the greatest problem in these transplantations due to severe adverse effects, mainly the possibility of malignant tumours and opportunistic infections and it is the strongest argument of the opponents. The advocates claim that even kidney or pancreatic transplant is not a life saving procedure and it is only based on the will of the patients, whether they want to proceed with the therapy after thorough information about the risks. In spite of ethical disputes among lay and expert community are these procedures performed, patients after surgery report positive feedback in vast majority. The question whether these procedures should be performed or not is currently being replaced by the questions how to perform it the best and safe.

Declaration of interest: Author has no financial or other interests related to the content of this article.

Corresponding author:

Martin Molitor, M.D., PhD.

Department of Plastic Surgery

Hospital na Bulovce and the First Faculty of Medicine, Charles University

Budínova 2, Prague 8, 181 10

Czech Republic

E-mail: martinmolitor1@gmail.com