COMPOSITE TISSUE ALLOTRANSPLANTATION AND RECONSTRUCTIVE SURGERY: The first clinical applications

COMPOSITE TISSUE ALLOTRANSPLANTATION AND RECONSTRUCTIVE SURGERY:
The first clinical applications

François PETIT

Plastic Surgery Research Laboratory
Massachusetts General Hospital - Harvard Medical School,
Boston, USA.

Department of Plastic Surgery
Hospital Henri-Mondor - University Paris-XII,
Créteil, France

On September, 1998, a 48-year old man with a right-hand amputation received a forearm transplant harvested from a 41-year old man in cadaveric (brain dead) status [1]. This first human hand transplantation was performed in Lyon, France by a team directed by J.-M. DUBERNARD. The procedure was not considered by all as an advance in hand surgery [2], but it will be remembered as a major step in the history of Man, as were the first kidney (Murray, 1954) and heart transplantations (Barnard, 1967). Dispute over whether or not the procedure was justified has already taken place in many publications [2-5]. Despite the contention, more hand transplants have been performed and other anatomic areas have been transplanted that recently have entered the scope of " composite tissue allotransplantation " (C.T.A.) - so called by its promoters - in the field of clinical practice.
CTA is not a new technique, but a new practice, that couples the rules of microsurgical reconstruction and the rules of human organ transplantation. In its ambition (correction of physical handicaps), in its objective (reconstruction with anatomically identical structures), and in its technique (the transfer of vascularized tissues), CTA represents the essentiality of reconstructive surgery. However, by challenging the natural laws, composite tissue allotransplantation introduces a new dimension - immunologically, ethically and psychologically - that modifies the traditional rules of tissue reconstruction.
The first hand transplants have been regarded as uncustomary due to constraints, risks and uncertainty about their functional results. Simultaneously, the surgical community agreed about the prodigious potential that composite tissue allotransplantation might bring to tissue reconstructive surgery. The determinitive question to be addressed to the plastic surgeon not only concerns what the future of the first hand transplants entails, but also the prospect of all envisageable tissue allografts in the practice of reconstructive surgery. The main scientific data on this topic has been gathered and discussed here; it will help one make their own argument to this intentionally provocative question: " Is composite tissue allotransplantation the future of reconstructive surgery ? "

THE RULES OF ALLOTRANSPLANTATION IN RECONSTRUCTIVE SURGERY
In its broadest sense, tissue transplantation is the basis of all modern plastic and reconstructive surgery [6]. Nasal reconstructions with antebrachial flaps described by Tagliacozzi in the 16th century are still regarded as the founding acts of modern reconstructive surgery, which is based on the use of the patient's own tissues (so called " autologus ") transfered into the tissue defect. This kind of autotransplantation differs from tissue allotransplantation (formerly called homotransplantation) which is defined by the transfer of (allo)grafts harvested from a different subject in the same species (inter-human transplantation). Various techniques of tissue transplantation can also be differentiated by the location where tissues are transferred; the transfer is orthotopic when the graft is transfered to an identical anatomic site. It is heterotopic when donor and recipient sites are anatomically different. Thus, an autologus reconstruction is heterotopic.

Figure 1. Fra Angelico - San Marco Museum, Florence
Thirty five years ago, the mastery of microsurgery opened the field of replantation of amputated tissues and reconstruction by transfer of autologus free flaps [7]. Presently, the discovery of new immunosuppressive agents can extend this to tissue transfer between non-related subjects. From a surgical point of view, harvesting tissues from a cadaveric donor gives several advantages which free the surgeon from the major constraints of traditional reconstruction. First, tissue allotransplantation obtains the preeminent objective of any tissue reconstruction; the " like with like " replacement, … where a thumb would be reconstructed with a thumb but not with a toe. Accurate semantics actually dictates that we describe this practice as tissue replacement instead of tissue reconstruction. Another major advantage of allografts is the avoidance of any donor site morbidity which liberates the surgeon from the dilemma of healthy tissue destruction, a drawback of any reconstruction by autologus tissues. Vascularized tissue allotransplantation works on two parameters fundamental to any tissue reconstruction: improvement of the result and reduction of the morbidity related to donor site tissue harvesting. In doing so, it gives the surgeon the greatest technical conditions to reach the optimal physical, functional, aesthetic and psychological result from a tissue reconstruction. Even compared to amputated tissue replantation, allotransplantation offers theoretical advantages that would give an improved functional and aesthetic result (table I). This distinction is restricted to the surgical or " technical " aspect of the procedure and does not consider a major drawback, specific to inter-human transplantation : the need for an indefinite immunosuppressive treatment with potential side effects that currently restrict the development of allotransplation.

Table I

Comparison of different techniques in replantation or reconstruction for an amputated limb.

AUTO-REPLANTATION AUTO-RECONSTRUCTION ALLO-RECONSTRUCTION

Background emergency

accidental amputation of the graft

warm ischemia of the graft

predetemined level of replantation planned

-

-

- planned

surgical harvesting of the graft

cold ischemia of the graft

flexible level of replantation

Surgical procedure preparation + replantation

-

orthotopic transfer harvesting + shaping + implantation

donor-site morbidity

heterotopic transfer transplantation

-

orthotopic transfer

Result immediate

neurotized

preexisting aspect staged, alterations required

poor functional result

displeasing aspect immediate

neurotized

natural aspect

Composite tissue transplantation adheres to the trends of organ transplantation: harvesting from the donor in dead cerebral status, immunological incompatibility between donor and recipient, and life-long immunosuppression of the recipient. Attempts to obtain an efficient yet non-toxic immunosuppresive treatment has always been the limiting factor of organ transplantation. Introduced in 1982, cyclosporine dramatically improved the survival rate of patients by preventing graft rejection without medullar toxicity. Other immunosuppressive agents introduced in recent years (tacrolimus, mycophenolate mofetil, monoclonal antibodies, antilymphocytic immunoglobulins, …) have widened the therapies available to face any situation of rejection and have limited the toxic effects specific to each drug. Tissue transplantation benefited from the progress of immunosuppression but immunological specificities of composite tissues delayed the development of an efficient yet non-toxic protocol [8]. Unlike solid organ allografts, composite tissue allografts such as a hand or an entire limb, are histologically heterogeneous and are composed of tissues that express varying degrees of antigenicity. Among these tissues are skin and muscle, which are highly antigenic, and other immunocompetent components such as bone marrow and lymph nodes, which may participate in the immunological reaction [9]. Since 1990, many relevant studies have been conducted on animals and in 1997, a team from Louisville (KY, USA) demonstrated that an immunosuppressive tritherapy of tacrolimus, mycophenolate mofetil, and prednisone could prevent the rejection of an entire limb allograft without major toxicity in a preclinical model (adult swine) [10]. This new scientific data fortified the knowledge gained from thirty years of human limb (auto)replantation and in 1997, the specialists of tissue allotransplantation gathered at Louisville recommended the use of these immunosuppressive protocols to perform the first hand transplants in human [11]. Due to the complexity of the human immunological system, graft rejection, immunosuppressive toxicity and graft versus host disease (GVH) were still threats. The first hand transplants that have been performed in humans since 1998 have proved that the immunological obstacle can be overcome without major difficulties and that the graft is subjected to bone consolidation and tissue healing similar to the patient's own tissues. The amputation of the first hand transplant in February 2001, after a long period of mediatic wander for the patient, confirmed that rejection sanctions any breach of the immunosuppressive treatment, even 2 years and 4 months after the intervention.

THE FIRST CLINICAL APPLICATIONS
In 1988 and 1989, 10 years before the hand transplants, a french team directed by J.-C. GUIMBERTEAU performed 2 allotransplantations of the digital flexor tendon system harvested from a non-related living donor (whose 5th finger had to be amputated) and from a cadaveric donor. The grafts were revascularized onto the recipient's ulnar vessels [12]. Previously, non-vascularized allotransplants of fresh or frozen tendons had already been performed but the functional results of these allografts remained unsatisfactory due to the poor viability of the grafts and to the disorganization of the flexor system. The goal of the surgeons was to improve these results by transfering an entire flexor system (the tendon with its pulies and sheaths) in which viability had to be preserved by the immediate revascularisation of an anatomical pedicle. Thus, it was a true composite tissue allograft and rejection had to be prevented by an immunosuppressive regimen, despite the low antigenicity of the tendon tissue. A treatment with cyclosporine was prescribed at a non-toxic dose of 7 mg/day for a 6 month period. The grafts were accepted without rejection by the 2 recipients, the anastomosis of vessels remained permeable, and the active motion of these 2 fingers had improved from a range of zero to satisfactory.
In 1994, a german team directed by G. HOFMANN et M. KIRSCHNER started a program of vascularized bone tissue allotransplantations for sequelæs of chondrosarcoma or osteomyelitis of the inferior limb [13, 14]. Based upon the model of the first vascularized femoral diaphysis allograft performed by P. CHIRON in 1990 [15], 3 patients received a femoral diaphysis and 5 patients an entire knee joint with its extensor system. The grafts were harvested from patients in a brain dead status, resized to match the bone tissue defect, and transferred to the recipients. The grafts were immediately revascularized by anastomosis of their pedicle to the femoral vessels [16], and subsequently anchored to the femur and the tibia by a centromedullar nail. The immunosuppressive treatment began with the conjunction of cyclosporine, azathioprin, antithymocytic globulins, and methylprednisolone for the first 3 days, and was reduced to a bitherapy of cyclosporine and azathioprin. After 6 months, azathioprin was withdrawn and cyclosporine alone was administered until complete bone consolidation of the two osteotomies. The last clinical outcome published after a 2 to 5 year follow-up reported that 4 patients regained a favorable integration of their bone allograft and a satisfactory range of motion of their limb with a funtional knee joint [17, 18]. However, 1 femur allograft (among 3) and 3 knee allografts (among 5) became infected and were consecutively removed and replaced with a bone autograft or a full knee prosthetic device. These complications were attributed to an unsuitable immunosuppressive combination and to an inadequate adaptation of the immunosuppressive treatment further confounded by insufficient indications for monitoring the rejection process.

Table II

World experience in hand transplantation.

DATE SURGICAL TEAM POSTOPERATIVE FOLLOW-UP

September 1998 Lyon (France) Dubernard Unilateral removed (2 years, 4 m.)

January 1999 Louisville (USA) Breidenbach Unilateral 2 years, 6 m.

September 1999 Guangzhou (China) Pei Unilateral n1
Unilateral n2 1 year, 10 m.

January 2000 Lyon (France) Dubernard Bilateral 1 year, 6 m.

March 2000 Innsbrück (Autria) Pazzi Bilateral 1 year, 4 m.

May 2000 Kuala-Lumpur (Malaysia) ? Unilateral 1 year, 2 m.

August 2000 Monza (Italy) Lanzetta Unilateral 1 year

October 2000 Guangzhou (China) Pei Bilateral 9 months

January 2001 Harping (China) ? Bilateral 6 months

Febuary 2001 Louisville (USA) Breidenbach Unilateral 5 months

The functional results of the first 4 patients (in bold) have been evaluated and compared in May 2000, and published in the journal of MICROSURGERY [22].

Since September 1998, 11 hand transplants have been performed around the world, among them 4 were bilateral (table II) [1, 19, 20]. The observations and results of the first 4 unilateral allografts were gathered and assessed during the 2nd International Symposium on composite tissue allotransplantation (Louisville, USA, May 2000), and published in the journal MICROSURGERY [21]. At this time, the follow-up was 8 to 20 months. The comparison of these 4 cases illustrates the conditions under which the procedures were performed by 3 different teams and gave an initial glimpse into the functional results of these grafts. The grafts were harvested at a location above the elbow on the 4 donor subjects and stored at 4°C during 6 to 12 hours (cold ischemia time) preceded by perfusion of the brachial artery with the customary preservation solution for organ transplants (solution from the University of Wisconsin). Distal extremities of the stumps on the recipients were resected until identification of the healthy anatomical structures was acheived. Both of the two bones within the grafts were shortened and adhered to the recipient bones before the vascular, tendon and nerve anastomosis. The level of the nerve anastomosis was kept as distal as possible (from 21 cm to 1 cm from the wrist palmar fold) to reduce the time of nerve regeneration. A skin autograft (Lyon, Louisville) and a tendon autograft (Louisville) harvested from the foot have sometimes been necessary. The 4 patients received an induction immunosuppressive treatment for the first 7 to 10 days, followed by a maintenance therapy with the identical immunosuppressive combination of tacrolimus, mycophenolate mofetil, and prednisone. The patients that had been operated in Lyon and in Louisville faced a few episodes of moderate rejection several months after the operation that were diagnosed with the observation of an erythema on the grafted hand, and ultimately confirmed with skin biopsies. The rejection was controlled in all cases with a bolus of oral prednisone and with tacrolimus ointment. The 2 patients operated in China did not experience any rejection during the first 8 months of follow-up, perhaps because of higher immunological compatibility (3 HLA mismatches, versus 6 for the Lyon and Louisville patients), initial irradiation or mechanical removal of the bone marrow contained in the diaphyses of the 2 bones of the graft, or the higher dosage of steroids used in the maintaining treatment. The functional recovery of the first 4 hand transplants was evaluated in May 2000 . It was considered " fair " (Louisville, Guangzhou 1) and " good " (Guangzhou 2) by the Carroll test, which assesses the global functional capabilities of the upper limb in the everyday use (table III) [22, 23]. The patient transplanted in Lyon did not perform the Carroll test but exhibited poor functional capacity. The nerve regeneration, a key determinate of functional recovery, was evaluated by the Tinel test and was considered remarkably rapid during the first few months for the 4 patients [24]. This observation was attributed to the favorable effect of tacrolimus on axonal regeneration, a phenomenon that was previously observed in animals and in humans [25-28]. However, nerve regeneration was neither linked to reinnervation of the intrinsic muscles, nor to a satisfactory distal sensitivity indicated by the Semmes-Weinstein test [29]. While the patient operated in Lyon ceased physical therapy, the surgical teams in Louisville and Guangzhou are still hoping to improve the functional results of the allografts with a program of physical therapy extended for more than 2 years postoperatively [30]. Though anticipatory and limited, these functional results are encouraging, but they should not conceal the repercussions of the immunosuppressive treatment. During the first 8 to 20 months postoperatively of the first 4 hand transplanted patients, the following complications were observed: insulin-dependent diabetes mellitus (Lyon), Cushing's syndrome (Guangzhou 1), CMV colitis (Louisville), herpetic cutaneous infections (Lyon) and recurrent cutaneous mycoses (Louisville, Guangzhou 1). All these complications were treated and overcome with a decrease in immunosuppression, but their recurrence and likely manifestations could have affected the quality of life. On February 2, 2001, the first hand transplant was amputated [31]. The patient never followed his treatment nor his physical therapy. He did not tolerate his diabetes very well and the poor functional results disheartened him. Two years postoperatively, the patient definitively discontinued his immunosuppressive treatment and the graft was finally rejected in a few weeks. He has since recovered from his previous conditions and is now free of medications. The other 7 patients uni- or bilaterally hand transplanted around the world are still living with their graft and are strictly following their immunosuppressive treatment and physical therapy.
Tableau III

Score of the Carroll test, that serves as an evaluation of the functional capacities of the hand in everyday life utilization (according to Russell [23]).

85 Excellent 99

75 Good 84

51 Fair 74

0 Poor 50

A prosthesis usually scores 25 or less.
The best replantations score within the 70 range.

In a field where the results have long been discouraging, new nerve allografts recently have given hope to patients suffering from extended peripheral nerve defects [32]. The team lead by S. MACKINNON (St-Louis, USA) presented results of peripheral nerve allotransplantations on a series of 7 patients ranging from 3 to 24 years old, operated on between 1988 and 1998 following upper limb (4 patients) or lower limb (3 patients) impairing traumas [28]. The grafts were harvested from limbs of subjects in the brain dead status and preserved via cold ischemia at 5°C for 7 days prior to implantation. The allografts, with an average length of 190 cm (range: 72 and 350 cm), were eventually completed with crural nerve autografts. The first 5 patients received a treatment of cyclosporine, azathioprin and prednisone; tacrolimus replaced cyclosporine for the last 2 patients. The immunosuppressive therapy was maintained until evidence of nerve regeneration distal to the graft (positive Tinel test) was observed, with an average time of 18 months (range: 12 to 26 months). One of the patients displayed a total immunological rejection of the grafts 4 months postoperatively, which was attributed to the underdosage of cyclosporine. All the other patients (6) recovered a sensitivity and some (3) recovered a motility (upper limb grafts only) which was unaltered subsequent to the withdrawal of immunosuppression. No side-effects directly related to the immunosuppressive treatment were observed. These clinical results were made possible by an improved knowledge of the regeneration process of nerve allografts in animals, and particularly by the observation of the replacement process of nerve cells in the graft by Schwann cells of the recipient [33]. The inducing effect of the tacrolimus on regeneration could have also been assistive [25, 26]. The withdrawal of the immunosuppressive treatment after the initial induction period avoided any iatrogenic complications. Despite specific conditions that are nonapplicable to other tissues (the non-vascularization of the grafts, the use of interposition grafts but not " terminal " grafts, preservation before implantation, and withdrawal of the immunosuppressive treatment), these nerve allografts represent an advance in the field of nerve regeneration that will directly benefit composite tissue allografts such as the hand.
One of the most exciting applications of vascularized tissue allotransplantation in functional reparative surgery is that of the first larynx allograft performed in January 1998 by M. STROME at the Cleveland Clinic (Cleveland, OH, USA) [34]. A 40 year old man, aphonous since the age of 20 after the traumatic avulsion of his larynx, received an allograft of the complete pharyngo-laryngal system (larynx, pharynx, 6 laryngeal rings, 2 superior and recurrent laryngeal nerves, superior thyroid arteries, right internal jugular vein and left middle thyroid vein, thyroid and parathyroid glands). After a 10 hour cold ischemia time, the graft was revascularized on the recipient by the right vessels. It was suspended to the hyoid bone superiorly, sutured to the 5th tracheal ring inferiorly and to the esophagus posteriorly, followed by the anastomosis of the left vessels prior to the 2 laryngeal nerves and right recurrent nerve. The recipient's left recurrent nerve could not be identified. The patient received an intial treatment of monoclonal antibodies OKT3, cyclosporine, mycophenolate mofetil, and methylprednisolone, followed by a maintainance therapy of tacrolimus, mycophenolate mofetil and prednisone. A rejection episode at 15 months postoperatively, diagnosed by an aphony and laryngeal swelling, was confirmed by laryngeal biopsies and treated in a few days with a transient increase of the steroids doses. The patient exhibited high blood pressure for 6 months, treated by anti-hypertensive drugs, and 3 episodes of tracheobronchitis treated by antibiotics. A pulmonary infection of Pneumocystis carinii occurred after the patient unexpectedly discontinued his preventive treatment and was treated with antibiotics. All these complications were attributed to the immunosuppressive treatment. Thyroid and parathyroid hormonal dosages remained normal after the transplantation. The functional results were published recently as a clinical report, three and a half years postoperatively [35]. At 16 months postoperatively, the various parameters of the voice (tone, quality, intensity, flow, and respiratory coordination) were normalized. The patient currently talks with a perfectly intelligible voice with a natural aspect. The patient obtained efficient deglutition after 3 months. He can now feed himself without inhalations. The taste and odor sensations have improved. No stenosis hampers the air flow and the tracheostomy will soon be closed.

THE FUTURE OF TISSUE ALLOTRANSPLANTATION
The first 25 cases previously discussed are currently the entirety of tissue allotransplantation for reconstructive surgery. Early results of these operations proved that vascularized composite tissue allotransplantation is now achievable. Graft survival - i.e. prevention of their immunological rejection - depends only on the adaptation of the immunosuppression that must be high enough and prolonged. New immunosuppressive agents are sufficient to extend survival of any kind of tissue graft including skin, which is seen as the most antigenic tissue, but they carry potential side-effects that limit their use in reconstructive surgery.
The first hand allografts were criticized by those who doubted the ability to functionally recover after the operation and opposed the procedure due to the risk of complications. Because having hands or a voice are noncritical to "life", it seemed unwarranted to subject handicapped but "healthy" patients to the risk of lethal complication, even a 1% risk [36]. Others who considered that the quality of life is an even more important consideration than just "staying alive", defended hand transplantations performed in a rigorous and scientific environment [37, 38].
Publication of the early results of the first tissue allografts changed the nature of the debate that was initially raised. These results are evaluated and compared every year during the International Symposium on Composite Tissue Allotransplantation . In May 2000, these results were deemed as encourageing for the quality of recovered function and for the tolerance to the immunosuppressive treatment which did not cause any major or irreversible complications [39]. Amputation of one of the hand transplants was executed in a patient that never submitted himself to the constraints inherent to the intervention (the physical therapy, the therapy observance, the side-effects of the treatment, and the close medical monitoring). This suggests that reversing the procedure remains a solution to potentially unacceptable complications or even for unsatisfied patients. The limited side-effects of the immunosuppressive treatment and the benefits of the transplantation - functional, but particularly psychological - manifesting from the restoration of body integrity confirm a posteriori that these operations were reasonnable, and even justified. However, composite tissue allotransplantation should still be regarded as an extreme solution for exceptional indications. In looking forward to long term results, the national committee of ethics in France has agreed to proceed to 5 more hand allotransplantations for double hand amputated patients [31].
The principle of "like with like" reconstruction, specific to tissue allotransplantation, gives hope to the broadening of the "field of possiblity" in reconstructive surgery to physical handicaps with no current solution. The use of vascularized tissues harvested from a different subject could theoretically be extended to all reconstructive surgery with autologus tissues to obtain better functional and æsthetic results and to reduce the morbidity from tissue harvesting. Practically, application of tissue allotransplantation is currently restricted to rare situations by:
1 - the constraints of inter-human transplantation: the side-effects of immunosuppression (metabolic disorders, malignancies, infections) are the predominant limiting factor in tissue allotransplantation for reconstructive surgery. The risk of transmitting infection that might elude from current techniques of detection should not be ignored. In addition, the indispensable matching of donor and recipient under cosmetic criteria (gender, ethnic background, morphology) is complicated by the current lack of organ and tissue donors in some countries.
2 - the difficulty in selecting the appropriate indications: success of these operations relies upon the selection of justified indications, on an efficient immunosuppressive protocol and on the observance of the treatment and physical therapy by the patient. Reconstructive surgeons have to define which physical handicaps justify a reconstruction with an allotransplant. Scalp avulsions, extended facial burns, large mandibular exereses and proximal limb amputations (preferably at the upper limb) have already been suggested and some have been experimented in animals [40]. On the contrary, allotransplantation is unsuitable for certain pathologies: breast reconstruction, for example, would not be justified nor technically feasible considering the difficulty to withhold a breast based on a reliable vascular pedicle. Likewise, an allograft would not be suitable for congenital malformations of the limb because their functional result would be poor for these children who do not feel the lack of a missing limb or hand.
3 - the uncertainty over the long term results: while the functional results of these allografts should improve with time and physical therapy, some immunological phenomenons might curtail these results in the long term. In organ transplantation, the functional capacities of some grafts (mostly kidney and heart allografts) decrease with time : 15 years postoperatively, an average of 35% of the grafts are not functional [41]. This phenomenon is not clearly understood and is termed "chronic rejection". Possible explanations are: latent immunological rejection, toxicity of the immunosuppressive treatment, and early aging of the grafts. It is anticipatory to know if composite tissue allografts will undergo this phenomenon, but it is a serious threat to the long term functional capacities of these allografts. The quality of the functional results also depends on the integration of the graft in the body identity of the transplanted patient, i.e. the recognition and the acceptance of the graft as "self". Functional MRIs performed on the patient who received a double hand transplant in Lyon in January 2000 (figures 2 and 3) showed that the cerebral motor cortex is able to restructure itself to recognize and activate the transplanted hands, even after the long period of sensitive deprivation due to the amputation [42]. This cerebral plasticity is a key factor for the use of the hands in everyday life, but it does not presage the psychological acceptance of the grafts, which no animal study can evaluate. A risk exists that the patient becomes preoccupied with the foreign origin of the graft, which may lead to its "psychological rejection", as after some cosmetic surgery procedures.

Figures 2and 3. Denis C…, 35 years-old,
before (2000) and after (2001) a double hand transplantation performed in Lyon (France) in January 2000.
(Photos due to the courtesy of Prof. J.-M. DUBERNARD)

CONCLUSION
Vascularized composite tissue allotransplantation is a tremendous hope for reconstructive surgery. The early results of the first clinical cases are encourageing - very exciting in some cases - but will have to be evaluated and confirmed in the long term. Meanwhile, this new procedure should not be forbidden nor recommended, but reserved for a few teams that are experienced in both reconstructive and transplantation surgery. Restricted to major handicap conditions and performed under the fundamental guidelines of medical ethics - professional competency, therapeutic objective, and information of the patient - composite tissue allotransplantation is a rightful expression of reconstructive surgery [43].

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Maîtrise Orthopédique n°111 - 2002; Febuary.