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Vascularized Composite Allotransplant in the Realm of Regenerative Plastic Surgery

      Abstract

      Vascularized composite allotransplant (VCA) has led to new treatment options for patients with severe upper extremity and facial injuries. Although VCA can restore form and function, it exposes the patient to the risks associated with lifelong immunosuppression. Hopefully, ongoing advances in regenerative medicine will someday obviate the need for VCA, but until that time, VCA remains an immediate means of reconstructing otherwise unreconstructable defects. We review the outcomes of hand and face transplants, as well as the recent developments in immunosuppression as it relates to the field of VCA.

      Abbreviations and Acronyms:

      DASH (Disabilities of the Arm, Shoulder and Hand), IRHCTT (International Registry on Hand and Composite Tissue Transplantation), OPTN (Organ Procurement and Transplantation Network), SOT (solid organ transplant), UNOS (United Network for Organ Sharing), VCA (vascularized composite allotransplant)
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      Learning Objectives: On completion of this article, you should be able to (1) define the indications for vascularized composite allotransplantation, (2) describe the outcomes and indications of hand transplantation to date, and (3) describe the outcomes of face transplants to date.
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      Advances in regenerative medicine have led to new options for reconstruction of devastating soft tissue defects due to trauma, congenital deformities, and neoplastic conditions. Among the most promising advances within the realm of regenerative and restorative surgery is the advancement of hand and face vascularized composite allotransplant (VCA), which now allows for the reconstruction of wounds that previously would have been treated with prostheses or multistage flap reconstructions. Similar to solid organ transplant (SOT), VCA consists of the transfer of living tissue from a donor to a recipient. The transplanted hand or face contains a composite of tissue types including skin, bone, muscle, tendon, and nerve and requires a vascular connection for survival. In comparison with SOT, in which the organ is fully functional at the time of revascularization, hand and face transplants require nerve regeneration into the transplanted tissue for the reestablishment of sensation within the skin and reanimation of muscles. Following VCA, patients require lifelong immunosuppression to prevent rejection. Vascularized composite allotransplants should be differentiated from acellular allografts, which have been used for several years as nonvascularized structural grafts, such as tendon grafts and bone allografts.
      • Amer H.
      • Carlsen B.T.
      • Dusso J.L.
      • Edwards B.S.
      • Moran S.L.
      Hand transplantation.
      The history of VCA extends back to 1964 when the first hand transplant was attempted, just 10 years after the first successful kidney transplant was performed in 1954.
      • Merrill J.P.
      • Murray J.E.
      • Harrison J.H.
      • Guild W.R.
      Successful homotransplantation of the human kidney between identical twins.
      Since 1954, SOT has become a mainstay of treatment for end-stage disease of the kidneys, pancreas, liver, heart, and lungs, but it has just been within the past decade that hand transplant has become a more established means of hand reconstruction.
      • Sayegh M.H.
      • Carpenter C.B.
      Transplantation 50 years later—progress, challenges, and promises.
      • Morris P.J.
      Transplantation—a medical miracle of the 20th century.
      For many decades, VCA was not thought to be feasible because of the high antigenicity observed within the skin.
      • Murray J.E.
      Organ transplantation (skin, kidney, heart) and the plastic surgeon.
      Early failure with hand transplant helped to perpetuate this notion because the first hand transplant, performed in Ecuador, failed due to inadequate immunosuppression.
      • Gilbert R.
      Transplant is successful with a cadaver forearm.
      • Gilbert R.
      Hand transplanted from cadaver is reampuated.
      At that time, azathioprine and hydrocortisone were the main drugs for immunosuppression, resulting in an 80% incidence of acute rejection in renal transplant recipients and a 40% incidence of renal graft survival at 1 year
      • Zand M.S.
      Immunosuppression and immune monitoring after renal transplantation.
      (Figure 1).
      Figure thumbnail gr1
      Figure 1One-year first cadaveric renal allograft survival and rejection episodes over time. The figure illustrates the best reported 1-year cadaveric renal allograft survival and incidence of rejection over a 45-year period. The time that various immunosuppressive medications were introduced is indicated by their position on the graph. AZA = azathioprine; CY-A = cyclosporine A; FTY720 = fingolimod; 6-MP = 6-mercaptopurine; MMF = mycophenolate mofetil.
      From Semin Dial,
      • Zand M.S.
      Immunosuppression and immune monitoring after renal transplantation.
      with permission.
      With advances in immunosuppression, particularly the introduction of calcineurin inhibitors (cyclosporine) and potent antibody-based induction therapy, the first successful hand transplant was performed in 1998 in Lyon, France, under the direction of Jean-Michel Dubernard.
      • Dubernard J.M.
      • Owen E.
      • Herzberg G.
      • et al.
      Human hand allograft: report on first 6 months.
      Success with other hand transplants over the past decade has ushered in the modern era of VCA; this period has been highlighted by the first successful partial face transplant occurring in 2005.
      • Dubernard J.-M.
      • Lengelé B.
      • Morelon E.
      • et al.
      Outcomes 18 months after the first human partial face transplantation.
      To date, 89 upper extremity and 27 face transplants have been performed.
      • Siemionow M.
      • Gharb B.B.
      • Rampazzo A.
      Successes and lessons learned after more than a decade of upper extremity and face transplantation.
      In recent years, several hospital systems have adopted VCA as a treatment option for complex hand and face injuries. During 2010 to 2013, the number of face transplants more than doubled from 13 in 2010 to 27 in 2013.
      • Siemionow M.
      • Gharb B.B.
      • Rampazzo A.
      Successes and lessons learned after more than a decade of upper extremity and face transplantation.
      Face transplants have been performed successfully in France, the United States, Spain, China, Turkey, Belgium, and Poland, offering hope for patients around the world with deformities that are not reconstructable with standard techniques.

      VCA and Regenerative Medicine

      It is hoped that tissue engineering and stem cell therapy will be able to produce organs and repair soft tissue defects without the need for immunosuppression. To date, unfortunately, tissue engineering has had limited clinical application because of difficulties with vascularization, differentiation, and integration into host target tissue. Advances have been made with regard to tissue scaffolds, which can be used to reconstruct gaps in nerve or skin, allowing native tissue to fill the defect.
      • Karabekmez F.E.
      • Duymaz A.
      • Moran S.L.
      Early clinical outcomes with the use of decellularized nerve allograft for repair of sensory defects within the hand.
      • Iorio M.L.
      • Shuck J.
      • Attinger C.E.
      Wound healing in the upper and lower extremities: a systematic review on the use of acellular dermal matrices.
      The most recent success of bioengineered tracheal reconstruction has extended the limits of what was previously possible.
      • Lim M.L.
      • Jungebluth P.
      • Ajalloueian F.
      • et al.
      Whole organ and tissue reconstruction in thoracic regenerative surgery.
      • Macchiarini P.
      • Jungebluth P.
      • Go T.
      • et al.
      Clinical transplantation of a tissue-engineered airway.
      Stem cell seeding of bioengineered scaffolds is also limited by the inability to maintain target tissue phenotype and architecture. Larger tissue constructs are further hampered by the inability to supply adequate nutrient and waste exchange to the cells. Although there have been satisfactory outcomes with small nonvascular tissues for reconstruction, the development of a large engineered vascularized composite tissue block to restore a full face or a limb remains beyond our present reach; in contrast, VCA represents a novel mode of reconstruction for the present.
      • Orlando G.
      • Baptista P.
      • Birchall M.
      • et al.
      Regenerative medicine as applied to solid organ transplantation: current status and future challenges.
      • Bueno E.M.
      • Diaz-Siso J.R.
      • Sisk G.C.
      • et al.
      Vascularized composite allotransplantation and tissue engineering.

      Indications and Recent Developments in VCA

      Many injuries, particularly those sustained in the recent wars overseas, have defied current means of surgical reconstruction. Obvious examples include patients with bilateral hand amputations and severe facial injuries due to burns or trauma. In these cases, the extent of injury does not allow reconstruction of adequate form or function. At present, these injuries represent the best indications for VCA.
      All candidates for VCA must be educated about and/or try other reconstructive options before undergoing transplant. For unilateral and bilateral upper extremity amputees, there are many new options for prosthetic limbs that can improve function while avoiding the need for immunosuppression associated with VCA. Currently, upper limb prostheses are not able to return sensation, fine motor control, and the tactile aesthetics of human tissue.
      • Carlsen B.T.
      • Prigge P.
      • Peterson J.
      Upper extremity limb loss: functional restoration from prosthesis and targeted reinnervation to transplantation.
      Prosthetic and osteointegrated implants are also available for some facial defects such as the ear or nose, but facial prostheses cannot be fitted for total facial injuries and cannot restore normal speech, swallowing, or the ability to smile. Additionally, all prostheses are sensitive to natural daily occurrences, particularly sebaceous skin secretions along with daylight radiation (Figure 2). Nasal or ear prostheses can provide excellent aesthetic outcomes because they cover a limited area of the face that does not have considerable motion as compared with the perioral region or the cheek. A prosthesis that covers these areas may blend in well when the patient is in repose; however, with any motion of the facial muscles it becomes obvious that a prosthesis is in place (Figure 3).
      Figure thumbnail gr2
      Figure 2A 29-year-old man sustained a self-inflicted gunshot wound to the face several years ago. He had undergone mandible reconstruction as well maxilla reconstruction with vascularized fibula and iliac flaps. His nose was reconstructed with a prosthesis. A, New nasal prosthesis with excellent color match to native skin. B, Several months after wearing the prosthesis in the sun.
      Figure thumbnail gr3
      Figure 3Patient with a severe facial deformity caused by a blast injury. A, Reconstruction with a latissimus dorsi myocutaneous flap. B, After several debulking procedures, there was adequate space in the orbits and around the cheek and mouth to fit a prosthesis. C, Osteointegrated implants were placed to provide an anchor for a prosthesis. D, Face prosthesis. E, The face prosthesis in place looks good in repose. F, With animation, the prosthesis has an unnatural appearance.
      Unlike SOT, VCA requires nerve regeneration into the transplanted part for return of sensation and intrinsic muscle function. The degree, extent, and speed at which nerve regeneration occurs within the transplanted tissue will have a direct and critical effect on function. Incomplete regeneration of the ulnar nerve has resulted in suboptimal results for some hand transplant recipients, particularly those with transplants proximal to the elbow.
      • Landin L.
      • Bonastre J.
      • Casado-Sanchez C.
      • et al.
      Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review.
      • Glaus S.W.
      • Johnson P.J.
      • Mackinnon S.E.
      Clinical strategies to enhance nerve regeneration in composite tissue allotransplantation.
      Because of the necessity for nerve regeneration following transplant, patients with preexisting neuropathies that could adversely affect the recovery of sensation or motor function within the hand or face should be cautioned against transplant. Conditions such as inherited peripheral neuropathy, inflammatory (axonal or demyelinating) neuropathy, systemic disease with associated neuropathy (diabetes, alcoholism, amyloidosis), and toxic neuropathy (eg, heavy metal poisoning, drug toxicity, industrial agent exposure) should be considered relative contraindications for VCA.
      • Amer H.
      • Carlsen B.T.
      • Dusso J.L.
      • Edwards B.S.
      • Moran S.L.
      Hand transplantation.
      Additional exclusion criteria for VCA are the same as for SOT, including uncontrolled hepatitis B or C infection, viral encephalitis, or malignant disease.
      Absolute inclusion and exclusion criteria have not been clearly established for face transplant candidates. Patients with severe burns, trauma, and neurofibromatosis have all been considered for transplant. Generally speaking, indications for transplant include (1) severe facial injury resulting in the inability to perform the critical functions of speech, eating, and chewing, and loss of sphincter functions (orbicularis oris and oculi) because these functions are difficult to restore with conventional reconstructive techniques and (2) other injuries that are impossible to reconstruct with conventional techniques. Blindness has been considered a potential contraindication for face transplant due partially to the patient's inability to see the result of their transplant and to their inability to monitor for signs of rejection; however, a Boston group has disputed this claim, positing that these patients have motor and sensory recovery comparable to that of patients with preserved vision and are also able to comply with rehabilitation.
      • Carty M.J.
      • Bueno E.M.
      • Lehmann L.S.
      • Pomahac B.
      A position paper in support of face transplantation in the blind.
      Three of the 5 patients who have undergone transplant by the Boston group to date are legally blind. These patients have enjoyed the benefits of regaining functions they did not have before the transplant and of feeling “normal.” One patient stated that when she went to the supermarket before the transplant she would hear children whispering, and now she is just like everybody else.
      An important distinction between VCA and SOT is that VCA is not a lifesaving or life-prolonging procedure; it is a life-enhancing or life-giving procedure. Because of the requirements for immunosuppression, VCA may conversely shorten the life span of the transplant recipient.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      A notable example of this potential complication is the second face transplant recipient from Lyon, France; this patient received an Epstein-Barr virus–mismatched allograft and subsequently had posttransplant lymphoproliferative disorder and Epstein-Barr virus–induced leiomyosarcoma.
      • Conrad A.
      • Brunet A.S.
      • Hervieu V.
      Epstein-Barr virus-associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient.
      Candidates for VCA must be willing to undergo lifelong immunosuppression and follow rehabilitation protocols after allotransplant.
      • Amirlak B.
      • Gonzalez R.
      • Gorantla V.
      • Beidenbach III, W.C.
      • Tobin G.R.
      Creating a hand transplant program.
      In general, these are physically healthy patients without major comorbidities. Although physically healthy, many patients have psychiatric disorders associated with the trauma of the inciting event and also the stigma of their injury. Many patients with major tissue defects may live in isolation and exhibit dependence on others for activities of daily living. In addition, many of these patients may have depression and substance abuse due to intractable pain. The Innsbruck Psychological Screening Program for Reconstructive Transplantation has been described as a tool for assessment of psychiatric health in potential VCA recipients.
      • Kumnig M.
      • Jowsey S.G.
      • Rumpold G.
      • et al.
      The psychological assessment of candidates for reconstructive hand transplantation.
      Although national and multinational organizations such as Eurotransplant in Europe and the United Network for Organ Sharing (UNOS) provide guidelines and rules for allocation of solid organs, mandatory registries for VCA do not yet exist. Furthermore, considerations for VCA donors exceed those for SOT, with potential donors needing to fulfill requirements such as similarity of skin color, gender, and age matched to recipients for hand and face transplant.
      • Weissenbacher A.
      • Hautz T.
      • Pratschke J.
      • Schneeberger S.
      Vascularized composite allografts and solid organ transplants: similarities and differences.
      Thus far, donors and recipients have not been matched for HLA antigen. Avoidance of mismatches to preexisting anti–HLA antibodies has generally been undertaken. The extent of HLA mismatching has been linked to acute rejections as well as graft vasculopathy.
      • Bonastre J.
      • Landin L.
      • Diez J.
      • Casado-Sanchez C.
      • Casado-Perez C.
      Factors influencing acute rejection of human hand allografts: a systematic review.
      • Schneeberger S.
      • Morelon E.
      • Landin L.
      ESOT CTA Committee. Vascularized composite allotransplantation: a member of the transplant family?.
      An important recent development is the decision by the US Department of Health and Human Services to recognize VCAs as organs, and therefore the procedures will be regulated by the Organ Procurement and Transplantation Network (OPTN) and comply with rules and policies set by the OPTN contractor UNOS.

      Department of Health and Human Services. Final rule. Federal Register, The Daily Journal of the United States Government. 2013; 7/3:40033-40034-40042.

      With this decision, VCAs can now potentially be shared through the national UNOS system, therefore facilitating listing of patients and procurement of organs and potentially leading to an increase in the number of procedures that can be performed. Essentially, this recognition transforms VCA from an experimental procedure in the United States to an accepted procedure on a par with SOT. However, development of new policies that address the specific requirements of VCA will be needed.

      Overview of Hand Transplant and Outcomes

      Because hand and face allotransplants have been largely performed as isolated experimental procedures in various centers, communication between different groups has been essential in facilitating progress and monitoring outcomes. An important source of data is the International Registry on Hand and Composite Tissue Transplantation (IRHCTT), which is a voluntary registry that collects clinical information on VCAs. The most recent report of the IRHCTT was published in 2010 and provides follow-up data on 49 hand transplants in 33 patients.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      In total, there have been 89 hand transplants performed since 1998.
      • Siemionow M.
      • Gharb B.B.
      • Rampazzo A.
      Successes and lessons learned after more than a decade of upper extremity and face transplantation.
      The greatest number of transplants have been performed in the United States,
      • Bonastre J.
      • Landin L.
      • Diez J.
      • Casado-Sanchez C.
      • Casado-Perez C.
      Factors influencing acute rejection of human hand allografts: a systematic review.
      followed by China
      • Weissenbacher A.
      • Hautz T.
      • Pratschke J.
      • Schneeberger S.
      Vascularized composite allografts and solid organ transplants: similarities and differences.
      and Poland.
      • Dubernard J.M.
      • Owen E.
      • Herzberg G.
      • et al.
      Human hand allograft: report on first 6 months.
      Successful replantation of fingers, thumbs, hands, and forearms have all been reported since the 1960s,
      • Malt R.A.
      • McKhann C.F.
      Replantation of severed arms.
      • Tamai S.
      Twenty years' experience of limb replantation—review of 293 upper extremity replants.
      • Matsuhara K.
      • Tamai S.
      • Fukunishi H.
      • Obama K.
      • Komatsu S.
      Experience with reanastomosis of the amputated thumb.
      and established outcome scores for the evaluation of these patients' function have been applied to hand transplant recipients. In 2008, Breidenbach et al
      • Breidenbach W.C.
      • Gonzales N.R.
      • Kaufman C.L.
      • Klapheke M.
      • Tobin G.R.
      • Gorantla V.S.
      Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant.
      reported that outcomes after VCA were similar to those after macroreplantation. Established patient-reported outcome scoring systems have been validated to allow for a more accurate assessment of VCA results. The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire has been provided to hand transplant recipients to gain objective and subjective data on the benefits of VCA. A decrease in the DASH score of more than 15 points has been found to represent a major improvement in hand function.
      • Solway S.
      • Beaton D.E.
      • McConnell S.
      • Bombardier C.
      The DASH Outcome Measure User's Manual.
      The IRHCTT report from 2010 provides good follow-up data on 49 hand transplants in 33 patients. Of these procedures, 16 were bilateral and 17 were single transplants.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      The mean age of the transplant recipients was 32 years (range, 19-54 years), and most (31) were male. The level of transplant was most commonly at the wrist (46%), followed by the distal forearm (19%), mid forearm (17%), proximal forearm (14%), and elbow (4%). Of these 33 patients, 31 had follow-up of at least 1 year. A good functional result was achieved in most patients, with 30 (91%) achieving tactile sensibility and 28 (85%) achieving discriminative sensibility (S4, 8 patients; S3+, 12 patients; S3, 12 patients).
      • Dellon A.L.
      • Curtis R.M.
      • Edgerton M.T.
      Reeducation of sensation in the hand after nerve injury and repair.
      Motor recovery commenced with the extrinsic muscles, followed by the intrinsic muscles at 9 to 15 months after transplant in most patients. Quality of life also improved in 75% of transplant recipients, allowing these individuals to return to work. Improvement of function after hand allotransplants was confirmed in a systematic review by Landin et al
      • Landin L.
      • Bonastre J.
      • Casado-Sanchez C.
      • et al.
      Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review.
      of 28 patients in whom the DASH score decreased by a mean of 27.6±19.04 points.
      Within the IRHCTT report, complications requiring surgical intervention included arterial thrombosis (n=2) and venous thrombosis (n=1) on postoperative day 1 as well as limited skin necrosis (n=6) and formation of multiple arteriovenous fistulas (n=1). Adverse effects related to immunosuppression occurred in numerous patients, with 29 having development of opportunistic infections such as cytomegalovirus or herpes virus infection and 23 experiencing metabolic complications such as transient hyperglycemia and increased creatinine concentration. Three patients required hypoglycemic agents on a permanent basis, and one patient had progression to end-stage renal disease requiring hemodialysis 8 years after the hand transplant. Transplant loss occurred in 3 patients: a bilateral hand transplant on day 45 due to bacterial infection, a unilateral transplant due to intimal hyperplasia on day 275, and another unilateral transplant due to nonadherence to immunosuppressive therapy 29 months postoperatively. One patient with bilateral hand and face transplants died on day 65 posttransplant due to cerebral anoxia.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      The Chinese experience is not included in the IRHCTT report but was later reported.
      • Pei G.
      • Xiang D.
      • Wang G.
      • et al.
      A report of 15 hand allotransplantations in 12 patients and their outcomes in China.
      In total, 15 transplants were performed in 12 patients from September 1999 to May 2008. The mean age of the recipients was similar to the IRHCTT cohort, 34 years (range, 19-52 years). Seven of these patients had their grafts removed, in all cases due to nonadherence to the immunosuppressive drug regimen. In addition, functional outcomes were overall poorer than those reported by other centers around the world.
      • Cavadas P.C.
      • Landin L.
      • Thione A.
      • et al.
      The Spanish experience with hand, forearm, and arm transplantation.
      • Schuind F.
      • Van Holder C.
      • Mouraux D.
      • et al.
      The first Belgian hand transplantation—37 month term results.
      • Jablecki J.
      • Kaczmarzyk L.
      • Patrzałek D.
      • Domanasiewicz A.
      • Boratyńska Z.
      First Polish forearm transplantation: report after 17 months.
      • Jablecki J.
      • Kaczmarzyk L.
      • Domanasiewicz A.
      • Chelmoński A.
      • Kaczmarzyk J.
      Unilateral hand transplant—results after 41 months.
      The results of bilateral above the elbow transplants were reported in 2012, after 19 and 30 months of follow-up.
      • Jablecki J.
      • Kaczmarzyk L.
      • Domanasiewicz A.
      • et al.
      Result of arm-level upper-limb transplantation in two recipients at 19- and 30-month follow-up.
      Both patients were able to flex the elbow with 160- and 180-degree range of motion in the fingers of the grafted limb, and DASH scores improved. Although there was delayed bony union in the posttransplant period, there was no evidence of acute or chronic rejection. However, both patients required additional surgical intervention to achieve wrist extension.
      Recent outcome data on unilateral hand transplants have revealed smaller improvements in DASH scores when compared with bilateral transplants, suggesting that larger functional improvements can be gained with bilateral transplants. In addition, all cases (to date) of rejection and amputation after nonadherence to immunotherapy have occurred in unilateral transplant recipients. This most recent data has led several European groups to consider unilateral transplant a relative contraindication for hand transplant. Although this decision is still controversial, the overall results of hand transplants performed to date have been positive, allowing recipients to return to work and support themselves independently.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      • Petruzzo P.
      • Dubernard J.M.
      The International Registry on Hand and Composite Tissue Allotransplantation.

      Overview of Face Transplant and Outcomes

      The goals of face transplantation are more complex than those for hand transplantation. Beyond functional restoration in the face (which includes swallowing, chewing, and speech), face transplantation aims to achieve a psychological change in patients and in the way that others perceive them so that recipients can reintegrate into society and resume normal lives. Unlike hand transplant, the recipient has no recourse beyond another face transplant in the case of graft failure. Depending on the defect that results from a graft failure, a patient may or may not survive. In many cases, the graft cannot be removed without life-threatening consequences; as a result, the ethics of face transplantation have been extensively debated.
      • Kalliainen L.K.
      Supporting facial transplantation with the pillars of bioethics.
      • Pirnay P.
      • Foo R.
      • Hervé C.
      • Meningaud J.P.
      Ethical questions raised by the first allotransplantations of the face: a survey of French surgeons.
      To date, 28 face transplants have been reported, and 3 additional transplants have been performed since that report.
      • Siemionow M.
      • Gharb B.B.
      • Rampazzo A.
      Successes and lessons learned after more than a decade of upper extremity and face transplantation.
      Five-year outcomes of the first face transplant, performed in 2005, were recently reported.
      • Petruzzo P.
      • Testelin S.
      • Kanitakis J.
      • et al.
      First human face transplantation: 5 years outcomes.
      Recipients continue to have a good aesthetic and functional results, with normal protective and discriminative sensibility as well as the ability to chew, swallow, smile, and blow normally. Despite 2 episodes of acute rejection during the first year after transplant, skin biopsy was normal at 5-year follow-up, with a slight perivascular inflammatory infiltrate detected on a mucosal biopsy specimen. The main consequence of immunosuppression was a progressive decrease in renal function, as well as arterial hypertension, hyperlipidemia, mild cholangitis, an episode of bilateral pneumonia, and cervical carcinoma in situ. These adverse effects were partially managed through switching medication from tacrolimus to sirolimus and other therapies.
      A review of 21 face transplants was reported by Shanmugarajah et al
      • Shanmugarajah K.
      • Hettiaratchy S.
      • Butler P.E.
      Facial transplantation.
      in 2012. Overall, sensory recovery of the allografts has been good, with early recovery of mechanical and thermal sensibility and full restoration of sensation by around 8 months. Motor recovery has been slower than sensory recovery. Recipients recover the ability to smell, eat, drink, smile, and speak, and removal of scarred tissue during the transplant procedure has reduced chronic pain. Although episodes of acute rejection have been common, they have been controlled with adjustments to immunosuppressive medication, and no episodes of chronic rejection have been reported. Psychological outcomes after face transplant have been reported, with improvements in quality-of-life measures as well as indices assessing appearance, self-image, and facial anxiety.
      • Chang G.
      • Pomahac B.
      Psychosocial changes 6 months after face transplantation.
      • Coffman K.L.
      • Siemionow M.Z.
      Face transplantation: psychological outcomes at three-year follow-up.
      Thus far, 3 deaths have occurred after face transplant, resulting in a mortality rate of 11.1% for the procedure.
      • Siemionow M.
      • Gharb B.B.
      • Rampazzo A.
      Successes and lessons learned after more than a decade of upper extremity and face transplantation.
      The first death occurred in the second face transplant recipient, who underwent the procedure in 2006 in China. The 30-year-old man had a partial face transplant after a bear attack and was nonadherent to immunosuppressive therapy. The second death occurred in a patient who had received the face transplant after treatment for head and neck cancer. The third death occurred in a patient who underwent a bilateral hand transplant and a face transplant simultaneously. This patient died of cerebral anoxia at 65 days posttransplant. Other complications were reported in 7 patients, including severe intraoperative bleeding (requiring transfusion of 66 U of packed red blood cells), acute respiratory distress syndrome, renal insufficiency, and jugular thrombosis.
      • Edrich T.
      • Cywinski J.B.
      • Colomina M.J.
      • et al.
      Perioperative management of face transplantation: a survey.
      • Sedaghati-nia A.
      • Gilton A.
      • Liger C.
      • et al.
      Anaesthesia and intensive care management of face transplantation.
      • Knoll B.M.
      • Hammond S.P.
      • Koo S.
      • et al.
      Infections following facial composite tissue allotransplantation—single center experience and review of the literature.
      Opportunistic infections were common in the Boston experience,
      • Knoll B.M.
      • Hammond S.P.
      • Koo S.
      • et al.
      Infections following facial composite tissue allotransplantation—single center experience and review of the literature.
      with cytomegalovirus being the most frequent organism, but were not associated with rejection.

      VCA in Other Areas

      Although hand and face transplants remain the best known applications of VCA, other allografts have been transplanted successfully. In 2006, the first unilateral lower limb allotransplant was performed at the pelvis level between 3-month-old ischiopagus conjoined twins.
      • Zuker R.M.
      • Redett R.
      • Alman B.
      • Coles J.G.
      • Timoney N.
      • Ein S.H.
      First successful lower-extremity transplantation: technique and functional result.
      • Fattah A.
      • Cypel T.
      • Donner E.J.
      • Wang F.
      • Alman B.A.
      • Zuker R.M.
      The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity.
      Hence, postoperative immunosuppression was not required. At 6 years posttransplant, the patient had good hip and knee flexion and knee extension and was able to walk and engage in sports with her peers. In addition, functional magnetic resonance imaging showed cortical integration of the limb. The second case performed to date involved a bilateral transfemoral lower extremity transplant to a 22-year-old patient from a full HLA-mismatched multiorgan donor.
      • de Lago M.
      World's first double leg transplantation is carried out in Spain.
      At 1-year follow-up, there was sensory regeneration to the malleolar level, and the patient had active knee extension and plantar flexion, allowing ambulation between parallel bars.
      • Cavadas P.C.
      • Thione A.
      • Carballeira A.
      • Blanes M.
      Bilateral transfemoral lower extremity transplantation: result at 1 year.
      Advocates of lower extremity transplant cite the morbidity associated with amputation, such as the inability of many patients to return to work and the high incidence of psychological disorders such as depression, anxiety, and substance abuse in amputees.
      • McCarthy M.L.
      • MacKenzie E.J.
      • Edwin D.
      • Bosse M.J.
      • Castillo R.C.
      • Starr A.
      LEAP Study Group
      Psychological distress associated with severe lower-limb injury.
      • Carty M.J.
      • Zuker R.
      • Cavads P.
      • Pribaz J.J.
      • Talbot S.G.
      • Pomahac B.
      The case for lower extremity allotransplantation.
      Because of the poor success with lower limb replants, the excellent prostheses available, and the high incidence of comorbidities such as diabetes and peripheral vascular disease in potential recipients, lower limb transplant remains a controversial topic.
      • Tukiainen E.
      • Suominen E.
      • Asko-Seljavaara S.
      Replantation, revascularization, and reconstruction of both legs after amputations: a case report.
      • Schmidhammer R.
      • Huber W.
      • Pelinka L.E.
      • Haller H.
      • Kroepfl A.
      Simultaneous bilateral lower leg replantation: evaluation by different scoring systems—a critical analysis.
      In our view, selection of recipients will have to be better defined and improvements in immunosuppression must be developed before lower limb transplant is performed routinely.
      One-year follow-up of the first successful uterus transplant from a multiorgan donor for restoration of fertility was reported in 2013.
      • Ozkan O.
      • Akar M.E.
      • Ozkan O.
      • et al.
      Preliminary results of the first human uterus transplantation from a multiorgan donor.
      The recipient had congenital uterovaginal agenesis and exhibited menarche 20 days posttransplant and regular monthly menstrual cycles subsequently. The recipient became pregnant in early 2013, but 8 weeks after pregnancy was confirmed no fetal heartbeat could be detected, and a miscarriage was suspected. Maintenance immunosuppression was similar to that for VCA, consisting of tacrolimus, mycophenolate mofetil, and prednisolone. Clinicians in Sweden have also successfully performed uterus transplant from live donors to recipients with absolute uterine factor infertility. To date, successful 6-month follow-up with a low-dose immunosuppressive protocol has been reported in 9 patients.
      • Brännström M.
      • Johannesson L.
      • Dahm-Kähler P.
      • et al.
      First clinical uterus transplantation trial: a six-month report.
      • Brännström M.
      • Diaz-Garcia C.
      • Hanafy A.
      • Olausson M.
      • Tzakis A.
      Uterus transplantation: animal research and human possibilities.
      Another area in which VCA is being investigated is the abdominal wall.
      • Berli J.U.
      • Broyles J.M.
      • Lough D.
      • et al.
      Current concepts and systematic review of vascularized composite allotransplantation of the abdominal wall.
      This procedure has been performed successfully in combination with intestinal transplant, in which closure of the abdominal wall is extremely difficult.
      • Levi D.M.
      • Tzakis A.G.
      • Kato T.
      • et al.
      Transplantation of the abdominal wall.
      In combination with liver transplants, the posterior rectus sheath has also been transplanted successfully to aid closure of the abdomen.
      • Agarwal S.
      • Dorafshar A.H.
      • Harland R.C.
      • Millis J.M.
      • Gottlieb L.J.
      Liver and vascularized posterior rectus sheath fascia composite tissue allotransplantation.
      • Lee J.C.
      • Olaitan O.K.
      • Lopez-Soler R.
      • Renz J.F.
      • Millis J.M.
      • Gottlieb L.J.
      Expanding the envelope: the posterior rectus sheath-liver vascular composite allotransplant.
      Preclinical studies have investigated the utility of abdominal wall transplant to aid closure, in the absence of a concomitant visceral transplant.
      • Berli J.U.
      • Broyles J.M.
      • Lough D.
      • et al.
      Current concepts and systematic review of vascularized composite allotransplantation of the abdominal wall.
      • Jin J.
      • Williams C.P.
      • Soltanian H.
      • et al.
      Use of abdominal wall allotransplantation as an alternative for the management of end stage abdominal wall failure in a porcine model.
      Although this procedure is technically feasible, it cannot be justified currently because studies have not shown restoration of abdominal wall function and the requirement for long-term immunosuppression is an issue of concern.
      • Berli J.U.
      • Broyles J.M.
      • Lough D.
      • et al.
      Current concepts and systematic review of vascularized composite allotransplantation of the abdominal wall.
      Transplant of vascularized knee joints has been attempted, although with limited success. In a series of 6 patients, only 1 of 6 joints survived after 4 years, with 3 joints being lost to late rejection.
      • Diefenbeck M.
      • Wagner F.
      • Kirschner M.H.
      • Nerlich A.
      • Mückley T.
      • Hofmann G.O.
      Outcome of allogeneic vascularized knee transplants.
      The single surviving joint was lost at 56 months posttransplant due to graft vasculopathy and rejection.
      • Diefenbeck M.
      • Nerlich A.
      • Schneeberger S.
      • Wagner F.
      • Hofmann G.O.
      Allograft vasculopathy after allogeneic vascularized knee transplantation.

      Recent Developments in Immunosuppression

      Advances in immunosuppressive regimens have allowed transplant of vascularized composite allografts. Regimens used in many centers commence with induction therapy with antibody-based therapies such as anti–interleukin 2 receptor monoclonal antibodies, thymoglobulin, anti–CD52 monoclonal antibodies, or anti–CD3 monoclonal antibodies. Induction therapy is followed by maintenance immunosuppression with a combination of tacrolimus and mycophenolate mofetil with or without prednisone.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      • Diaz-Siso J.R.
      • Bueno R.M.
      • Sisk G.C.
      • Marty F.M.
      • Pomahac B.
      • Tullius S.G.
      Vascularized composite tissue allotransplantation—state of the art.
      These immunosuppression protocols were adapted from those used in SOT and have been noted to produce 96% hand transplant survival at 1 year.
      • Leonard D.A.
      • Kurtz J.M.
      • Cetrulo Jr., C.L.
      Vascularized composite allotransplantation: towards tolerance and the importance of skin-specific immunobiology.
      Corticosteroid-free maintenance immunosuppression is used by the Boston group, whereas other centers have substituted sirolimus, a mammalian target of rapamycin inhibitor, for tacrolimus to decrease adverse effects of medication, such as nephrotoxicity, impaired glucose tolerance, and chronic vasculopathy.
      • Diaz-Siso J.R.
      • Bueno R.M.
      • Sisk G.C.
      • Marty F.M.
      • Pomahac B.
      • Tullius S.G.
      Vascularized composite tissue allotransplantation—state of the art.
      • Chang J.
      • Davis C.L.
      • Mathes D.W.
      The impact of current immunosuppression strategies in renal transplantation on the field of reconstructive transplantation.
      Despite the success of these protocols, there has been a high incidence of acute rejection, with 85% to 90% of patients experiencing at least one episode during the first year posttransplant.
      • Petruzzo P.
      • Lanzetta M.
      • Dubernard J.M.
      • et al.
      The International Registry on Hand and Composite Tissue Transplantation.
      • Diaz-Siso J.R.
      • Bueno R.M.
      • Sisk G.C.
      • Marty F.M.
      • Pomahac B.
      • Tullius S.G.
      Vascularized composite tissue allotransplantation—state of the art.
      After some reported success of donor bone marrow infusions reducing the requirement for immunosuppression in SOTs and the reports of short-lived “nanochimerism” after the first face transplant, cell-based therapy was used by the Pittsburgh group to reduce the requirement for maintenance immunosuppression.
      • Petruzzo P.
      • Testelin S.
      • Kanitakis J.
      • et al.
      First human face transplantation: 5 years outcomes.
      • Fontes P.
      • Rao A.S.
      • Demetris A.J.
      • et al.
      Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation.
      • Ciancio G.
      • Miller J.
      • Garcia-Morales R.O.
      • et al.
      Six-year clinical effect of donor bone marrow infusions in renal transplant patients.
      • Schneeberger S.
      • Gorantla V.S.
      • Brandacher G.
      • et al.
      Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression.
      The Pittsburgh protocol involves infusion of unmodified donor bone marrow–derived cells on day 14 posttransplant after lymphocyte-depleting induction therapy with alemtuzumab. This is a time when the early inflammatory response to ischemia and reperfusion as well as the trauma of surgery has subsided. The underlying hypothesis behind cell-based therapy is that removal of circulating T cells with induction therapy followed by low-dose immunosuppression and bone marrow–derived cell infusion in the early posttransplant period increases the intrinsic tolerance potential of the allograft, leading to a state in which the recipient- and donor-derived immune cell clones can better accommodate each other.
      • Starzl T.E.
      • Murase N.
      • Abu-Elmagd K.
      • et al.
      Tolerogenic immunosuppression for organ transplantation.
      With a cell-based protocol, the Pittsburgh group was able to reduce maintenance immunosuppression to low-dose tacrolimus monotherapy only.
      • Schneeberger S.
      • Gorantla V.S.
      • Brandacher G.
      • et al.
      Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression.
      However, the data are from a single-arm study without a control group, and as such the results should be interpreted with caution. Patients were reported to have had acute cellular rejections that were treated, and thus they have not experienced donor-specific tolerance. As of the last report, none of the patients have been weaned from all their immunosuppressants, and one patient had his hand allograft removed because of rejection due to medication nonadherence. In addition, sustained microchimerism or macrochimerism was not detectable. This issue highlights a major difference between bone marrow therapy–based protocols used in VCAs and those recently reported in SOTs. Transient and stable mixed chimerism has been reported after kidney transplants, allowing weaning from all maintenance immunosuppression.
      • Kawai T.
      • Cosimi A.B.
      • Spitzer T.R.
      • et al.
      HLA-mismatched renal transplantation without maintenance immunosuppression.
      • Leventhal J.
      • Abecassis M.
      • Miller J.
      • et al.
      Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.
      It should be noted, however, that in the latter 2 studies, patients were recipients of live donor transplants that allowed extensive preconditioning of the recipient before transplant.

      Limitations of VCA and Future Developments

      The main impediment to more widespread adoption of VCA remains inadequate selection and preoperative counseling of recipients. Frequently, the reported cases of poor function and allograft loss have been attributed to medication nonadherence. The first successful hand transplant was lost due to a conscious decision of the recipient to discontinue immunosuppression. It has been well established that successful outcomes are dependent on a healthy physician-patient relationship. Klapheke et al
      • Klapheke M.
      The role of the psychiatrist in organ transplantation.
      • Klapheke M.M.
      • Marcell C.
      • Taliaferro G.
      • Creamer B.
      Psychiatric assessment of candidates for hand transplantation.
      reported the psychiatric results and observations obtained from the Louisville hand transplant experience. In these reports, Klapheke et al noted that the key indicators for success were the patient's ability to form alliances with their health care team, the patient's intellectual and emotional development, their sense of body image, and any component of untreated or ongoing posttraumatic stress disorder. Thus, further studies on the psychosocial implications of VCA are of utmost importance.
      Limitations of nerve regeneration will continue to limit VCA in upper extremity reconstruction to distal amputations. Proximal forearm or above elbow transplants have, for the most part, provided poor hand function and may not justify the risk of the procedure and the immunosuppression. Improvements in nerve regeneration will allow expansion of VCA to more proximal amputees who may in fact be in greater need given the limitations of prostheses for such proximal amputations. Improved nerve regeneration will likely also result in improved function for distal amputations as well as facial function.
      Although the need for lifelong immunosuppression is touted as a major impediment to expanding VCA to patients in need, the earlier VCA recipients have done very well, and in fact, to observers of the field, it appears that more recent transplants that have used novel immunosuppressive strategies have had less favorable outcomes. If transplant becomes possible without immunosuppression, that is, the goal of donor-specific tolerance is achieved with preserved immunocompetence, VCA will certainly benefit from this achievement, and more patients as well as health care professionals will find VCA acceptable. Currently, no tolerance-producing protocol has been expanded to the general transplant population. Current protocols have relied on transient or sustained chimerism and mandatory intense preparation of the recipient before transplant that require a living donor, a situation that is not possible in VCA.
      Attempts to translate animal studies to human VCA or to adapt experimental clinical protocols in SOT to VCA should be approached with extreme caution. In the SOT arena, developing adequately controlled and powered trials is extremely difficult. We would venture to say that it is impossible in VCA because of the small number of cases as well as the difficulty in establishing end points of function and controlling for such factors as the mass of tissues transplanted and the extent of muscle and nerve atrophy at baseline. We believe that until tolerance-producing protocols are in widespread use in SOT practice, they should not be attempted in human VCA.
      One promising area of research is the use of autologous, allogenic, or third-party mesenchymal stem cells to down-regulate the immune response and decrease ischemic reperfusion injury. Their use is still limited to experimental studies and trials, and some concerns have been raised in regard to safety and efficacy.
      • Le Blanc K.
      • Rasmusson I.
      • Sundberg B.
      • et al.
      Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.
      • Alagesan S.
      • Griffin M.D.
      Autologous and allogeneic mesenchymal stem cells in organ transplantation: what do we know about their safety and efficacy?.
      In animal models, treatment with bone marrow–derived mesenchymal stem cells was found to result in prolonged survival of VCAs, as well as development of stable and high-level chimerism.
      • Kuo Y.R.
      • Chen C.C.
      • Shih H.S.
      • et al.
      Prolongation of composite tissue allotransplant survival by treatment with bone marrow mesenchymal stem cells is correlated with T-cell regulation in a swine hind-limb model.
      • Plock J.A.
      • Schnider J.T.
      • Solari M.G.
      • Zheng X.X.
      • Gorantla V.S.
      Perspectives on the use of mesenchymal stem cells in vascularized composite allotransplantation.
      • Pan H.
      • Zhao K.
      • Wang L.
      • et al.
      Mesenchymal stem cells enhance the induction of mixed chimerism and tolerance to rat hind-limb allografts after bone marrow transplantation.
      The use of bioreactors for ex vivo allograft modulation before transplant has also been proposed to reduce antigenicity and enhance the function of grafts.
      • Rennert R.C.
      • Sorkin M.
      • Wong V.W.
      • Gurtner G.C.
      Organ-level tissue engineering using bioreactor systems and stem cells: implications for transplant surgery.
      Compared with SOT, the incidence of chronic rejection has been exceedingly low in VCA, with one case reported for hand transplant and none for face transplant.
      • Brandacher G.
      • Lee W.P.
      • Schneeberger S.
      Minimizing immunosuppression in hand transplantation.
      However, the number of recipients has been extremely small and the follow-up relatively short.

      Conclusion

      The field of VCA is in a phase of rapid development. Increasing clinical case volume, advances in immunosuppression, and legislative changes such as recognition of VCA by the OPTN promise greater availability of allografts as well as improved outcomes for patients. Vascularized composite allotransplant can serve as a reconstructive bridge until more advances are made in tissue engineering and regenerative medicine to reconstruct complex defects.

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      • Correction
        Mayo Clinic ProceedingsVol. 89Issue 8
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          In the article “Vascularized Composite Allotransplant in the Realm of Regenerative Plastic Surgery,” published in the July 2014 issue of Mayo Clinic Proceedings (2014;89(7):1009-1020), the affiliation should read: From the Essam and Dalal Obaid Center for Reconstructive Transplant Surgery, Mayo Clinic, Rochester, MN.
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