Transplantation in
plastic surgery
Dr. S. Vijay Kannan
History
In 1954, Dr. Joseph E. Murray, Plastic surgeon - first
successful kidney transplant between identical twins.
In 1958, human leukocyte antigen (HLA)
In 1960, 6-mercaptopurine and its precursor azathioprine
(AZT) by Charles Zukosi and Roy Calne
Nomenclature
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VCA - Vascularised Composite Allograft
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CTA - Composite Tissue Allotransplantation
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Autograft
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Isograft
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Allograft
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Xenograft
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Orthotopic - anatomically same
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Heterotopic - different site
Transplant Immunology
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The major histocompatibility complex (MHC) genes code the strongest
transplant antigens.
Human MHC molecules called human leukocyte antigens (HLAs) are
coded by a group of genes located on the short arm of chromosome 6.
MHC class I molecules (HLA-A, HLA-B, and HLA-C) are expressed on all
nucleated cells and generally present endogenous antigens
Class II molecules (HLA-DP, HLA-DQ, and HLA-DR) are constitutively
expressed only on antigen- presenting cells (APCs), including dendritic
cells, macrophages, and B-cells.
HLA match in kidney transplants is HLA-DR > HLA-B > HLA-A,
respectively.
NON-HLA ANTIGENS:
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ABO BLOOD GROUP ANTIGENS
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triggers hyperacute rejection of the organ due to the presence
of the preformed hemagglutinin A and/or B antibodies.
MINOR HISTOCOMPATIBILITY ANTIGENS
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Recognized by CD8 cytotoxic T-cells, leading to graft rejection.
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H-Y MiHA is encoded by the Y chromosome in males
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Mitochondrial proteins and enzymes
ALLORECOGNITION
PATHWAYS
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Direct pathway - recipient’s T-cells recognize the intact allogeneic HLAs
expressed by the donor cells.
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Immediate post-transplant period
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Acute cellular rejection
Indirect pathway - T-cells recognize peptides derived from the donor
HLAs presented by the recipient APC.
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Late onset of rejection & Chronic rejection.
Semi-direct pathway - the recipient dendritic cells or other APCs, acquire
the intact HLAs from the donor cells and present them to the recipient T
cells.
T-CELL ACTIVATION
B-CELL ACTIVATION
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B cells express antigen-specific receptors as immunoglobulins on their surfaces.
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When these receptors bind donor HLA antigens in the presence of helper T cells
(CD4 Th2) - B cells are activated.
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They divide, differentiate, and become plasma cells to secrete antibodies.
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Some activated B cells become memory B cells
HLA antibodies bind antigens and can cause graft injury
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activating the complement cascade (complement-dependent cytotoxicity)
via the Fc receptor on natural killer (NK) cells, neutrophils, and eosinophils
(antibody-dependent cellular cytotoxicity).
In addition to producing antibodies, B cells act as APCs. - Indirect pathway
REJECTION
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It is an inflammatory process developed by a specific immunologic response to the allograft
antigens.
85% of hand and face recipients experienced at least one episode of acute rejection in 1st yr
Hyperacute rejection - very rapidly within a few minutes after transplantation and represents
the classic example of the antibody-mediated rejection process
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associated with the preexisting antibodies against the MHC of donor cells.
Accelerated rejection - 24 h and 5 days post transplantation.
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The increased risk of developing an accelerated phase of rejection arises from sensitization
of the allograft recipient, for example, by a previous allograft.
classic, humoral mediated response; it precedes T-cell- dependent mechanisms, IgM, IgG,
C3, fibrin and leukocyte infiltrations
interstitial hemorrhages, vascular thrombosis, and leukocyte infiltrations.
ACUTE REJECTION
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Within a few days to a few weeks
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Cell-mediated process and arises from the activation of T cells
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Morphologic evidence of tissue injury: fibrinoid necrosis of arteries,
aggregation of the platelets leading to vascular obstruction.
Immunopathologic evidence: presence of complement factor 4 (C4)
deposition
Serologic evidence: circulating antibodies to the donor human
histocompatibility antigens (HLA) or other endothelial antigens
Components of acute composite allograft rejection include vasculitis,
dermatitis, myositis, and perineural involvement – confirmed through the
skin biopsy specimens.
CHRONIC ALLOGRAFT
VASCULOPATHY (CHRONIC
REJECTION)
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Slow process that occurs over months and/or years
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The frequency of chronic allograft vasculopathy correlates
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acute rejection episodes
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recipient sensitization
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insufficient MHC-antigen matching
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recipient age and race
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inadequate immunosuppression
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hypertension
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cytomegalovirus (CMV) infection/ reactivation
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prolonged ischemia time of the graft before transplantation
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smoking and hyperlipidemia.
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Endothelial injury of the affected
vessels
Inflammatory cascade, allograft
arteriosclerosis and graft fibrosis.
Cardinal feature : luminal
obliteration.
Blockage occurs due to the
proliferation of the smooth
muscle cells
Finally interstitial fibrosis leads to
allograft dysfunction.
IMMUNE TOLERANCE
The ultimate goal of transplantation science is to make genetically diffe
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Clonal deletion : T cells that express a TCR specific for a certain antigen are eliminated.
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Anergy: state in which T cells are alive but unable to respond to the antigen stimulation.
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occur in the thymus (central deletion) or extra thymically (peripheral deletion).
induced by the lack of co-stimulatory signals - leads to apoptosis.
Two major co-stimulatory interactions that take place between a T cell and antigenpresenting cell involve CD28/B7 and CD40L/CD40 pathways.
The blockade of these second signals using antibodies to specific receptors (CD40R,
B27) to induce a peripheral form of tolerance.
“Prope” (almost) tolerance - introduced by Calne
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defined as the donor- specific hypo responsiveness under a low dose of
immunosuppressive therapy.
leads to reduced immunosuppression-related side effects and allows for improved
allograft survival without episodes of acute or chronic rejection.
Immunotherapy
Immunosuppressive medications must inhibit the body’s
ability to reject a transplanted organ, but not at the expense
of the defense network against pathogens.
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Induction protocols : to prevent allograft recognition
during the peritransplantation period.
Maintenance regimen: to maintain the transplant.
Rescue agents : when ongoing rejection occurs, it is often
necessary to use to stop ongoing rejection and salvage a
transplant that would otherwise be lost.
Immunotherapy
Mechanism of action
SKIN TRANSPLANT
Skin allograft
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In large burns either in combination with autograft or in isolation.
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Along with autograft shows improved healing in comparison to autologous graft alone.
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Preservation with glycerol reduces the antigenicity of skin allografts and prolongs graft survival.
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Production of antibodies that may inhibit the possibility of future VCA.
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limiting factors: harvesting and banking services are not uniformly available, and significant risk
of disease transmission, susceptible to rejection
Skin xenograft
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Porcine xenograft has been used as a temporary dressing in large burns with seeding of
autologous grafts beneath it
limited use : susceptible to hyperacute rejection.
Bone allograft
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Frozen bone allograft commonly used for the reconstruction of long bone
defects
Acts as scaffold for ingrowth of osteocytic precursors that repopulate the
donor scaffold by creeping substitution.
Problems:
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susceptible to stress fracture and loosening of metal fixation devices.
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Vascularized allogeneic bone is susceptible to immunologic rejection.
Removal of marrow by irradiation or by replacement with recipient marrow
has been shown experimentally to prolong allograft survival.
Cartilage allograft
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Chondrocytes express HLA antigens on their surface and are
immunogenic & matrix is only weakly antigenic.
Surgical scoring or dicing with resultant exposure of allogeneic cells has
been shown to hasten reabsorption of allogeneic cartilage.
After irradiation pretreatment - used for volume augmentation in the facial
skeleton.
Initial good results in a large number of patients but long-term data
suggest a high rate of resorption.
Bovine-derived cartilage xenografts are susceptible to xenogeneic
mechanisms of rejection, which results in poorer outcome in comparison
to either allogeneic or autogenous cartilage grafts.
Nerve allograft
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Nerve autograft has a limited number of donor sites. In large nerve
defects, nerve allograft has been used in a small number of patients.
Immunologic rejection of nerve allograft can be prevented with
immunosuppression & decellularizing techniques
Immunosuppression needs to be administered only while the recipient
axons traverse the allograft and can then be terminated.
Decellularizing techniques : cold preservation, radiation, lyophilization,
and freeze thawing
Current clinical protocol involves 7 days of cold preservation of the nerve
allografts at 4–5°C in University of Wisconsin solution prior to implantation
HAND
TRANSPLANTATION
History
In 1964, the first hand transplant was performed by Dr. Gilbert in Ecuador.
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The patient was a bilateral upper extremity amputee that received a single hand
transplant. he was given azathioprine and prednisone for immunosuppression. The patient
experienced acute rejection and underwent amputation 3 weeks post-transplant.
In 1998, the first modern hand transplant was performed by Dr. Jean-Michel Dubernard and
colleagues in Lyon, France.
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The patient was a 48-year-old male amputation at the mid- forearm level in 1984. The
donor was a 41-year-old brain dead beating heart donor. The surgery was a technical
success, but the patient was non- compliant with his postoperative immunosuppression
and rehabilitation regimen and elected to have his transplanted hand amputated in 2001.
In 1999, second hand transplant by Dr. Warren Breidenbach and his team at the University of
Louisville.
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The patient was a 37-year-old male who lost part of his dominant forearm and whole
hand in a fireworks accident. He currently has the longest surviving transplant
Hand Recipient Criteria
Hand Donor Criteria
Pre OP workup
Team
Flow of events
1. PATIENT SCREENING
2. PREOPERATIVE PLANNING
3. CADAVER REHEARSAL
4. TEAM ASSIGNMENTS
5. OPERATING ROOM SET-UP
6. DONOR OPERATION
7. RECIPIENT OPERATION
8. POSTOPERATIVE COMPLICATIONS
9. REHABILITATION
10. OUTCOMES
Donor Operation
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Under tourniquet control
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Incision is outlined
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medial/volar component dissection down through
the nerves to the brachial artery/veins.
The brachial artery is isolated. It is ligated
proximally and distal control is obtained.
Cannulate the artery and this is secured with
suture. The veins are clipped or ligated proximally
and cut distally.
anterior to posterior dividing muscle
Disarticulation of elbow or osteotomy through the
humerus.
Back-table dissection: perfusion solution is instilled.
The solution is instilled until at least 500 mL have
been infused or all effluent is clear.
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Closure of the skin of the arm stumps.
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donor is then fitted with a prosthetic hand
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RECIPIENT
OPERATION
Standard incisions made 90° to the incisions used on the donor to
ensure Z-plasty such as interdigitation postoperatively.
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OSTEOSYNTHESIS
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MUSCLE/TENDON RECONSTRUCTION
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extensor reconstruction first followed by flexor reconstruction.
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NERVE RECONSTRUCTION
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REVASCULARIZATION
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no more than 7–8 h of cold ischemia have elapsed.
few vena comitans or deep veins and most superficial veins are
left open until after reperfusion has been performed to allow
efflux of the initially perfusing blood until the blood becomes
brighter red then remaining open veins are then anastamosed.
The final vein to artery ratio is typically 2 or 3 : 1.
SKIN CLOSURE
Immunotherapy
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Currently, there is no standard immunosuppressive regimen established
for extremity transplantation
Induction therapy : polyclonal (antithymocyte globulin, ATG) or
monoclonal (alemtuzumab or basiliximab)
Maintenance therapy with triple-drug therapy.
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Calcineurin inhibitor - to prevent early activation of T cells (e.g.,
tacrolimus)
Antimetabolite agent - to prevent lymphocyte proliferation (e.g.,
mycophenolate mofetil)
Steroid (e.g., prednisone).
Early Complications
Surgical
Medical
Vessel thrombosis
Pneumonia
Hematoma
Sepsis
Skin necrosis
Nonsurgical infections
Adverse medication
Arteriovenous fistulae
reactions
Acute limb loss
REHABILITATION
OUTCOMES
Hand Transplantation Score System,
HTSS.
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100-point scale that evaluates six
functional areas:
1. appearance (15)
A total score
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81 to 100 points - excellent
3. movement (20)
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61 to 80 - good
4. psychological and social acceptance
(15)
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31 to 60 - fair
5. daily activities and work status (15)
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0 to 30 - poor.
2. sensibility (20)
6. patient satisfaction and general wellbeing (15).
Face Transplant
History
The world’s first partial face transplant was done in
November 2005 - prof. Jean Michel Dubernard on a 38-yearold Isabella Dinoire after being bitten by a dog.
First, full-face transplant was done in 2010 by a team led by
Dr. Barret on Óscar who lost his facial structure by road
traffic accident
Types
Partial facial transplantation
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It consists of nose, lips, and amounts of chin and cheek.
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It requires sensory and motor nerve anastomoses
Full-face transplant
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It consists of whole face transfer from donor to recipient.
Classification
Indication
Patients having disfigured face by means of:
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Accidents/traumatic injury,
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Burn.
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Birth defects/congenital defects.
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Facial structures lost due to infection which are
untreatable with conventional surgical technique.
Recipient eligibility
Donor eligibility
Surgical team
Multidisciplinary approach
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Reconstructive surgeon - Plastic surgeon and oral &
maxillofacial surgery,
Orthodontist, psychiatrist, otolaryngologist, infectious
disease specialist, ophthalmologist
social worker, nutritionist, physiotherapist, pain medicine
specialist
Immunotherapy
OUTCOMES
Outcomes can be classified into several categories:
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Medical (immune-related, metabolic and hematologic
derangements, opportunistic infections, neoplastic growth)
Functional (speech, smell, airway, taste, mastication,
sensory reinnervation, facial animation, pain relief)
Aesthetic (patient and physician satisfaction, contour,
scarring, identity preservation)
Social (psychosocial reintegration, cost-effectiveness).
Benefits of facial
transplantation
1. Improved functionality
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ability to breathe, swallow, speak, smile, and show other emotions.
2. Rehabilitation of appearance
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Restoration of a near-normal facial appearance gaining the
confidence to return to their former lifestyles including social
activities and jobs.
3. Pain reduction and discomfort
Complications
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Mood swings following transplant surgery.
Psychiatric support must be proved to the patients before and
after partial facial transplantation.
Rejection.
Identity issues - will take up a new look different from donor or
recipient
Risks of taking transplant drugs for a lifetime
• Infections. • Diabetes.
LARYNGEAL
ALLOTRANSPLANTATION
Absence of a larynx is associated with the loss of a human sounding voice, an
impaired sense of taste and smell, a disposition to a high risk of lower
bronchoalveolar infection, and psychosocial disintegration.
The first clinical attempt at laryngeal transplantation was in 1969.
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A 62-year-old man with carcinoma of the larynx was the recipient of a
larynx from a 40-year-old donor. Unfortunately, the patient died due to
tumor recurrence at postoperative month 8.
The first successful laryngeal allograft procedure took place in 1998.
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The recipient was a 40-year-old man who had been in a road accident 20
years previously, resulting in laryngeal dysfunction. A laryngopharyngeal
complex, including thyroid, parathyroid, and five rings of the trachea was
transplanted.
INDICATIONS
Not a lifesaving one and is only intended to improve quality
of life.
The ideal recipients
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young trauma victims.
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large benign tumor
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low-grade malignant tumor resection.
DONOR PROCEDURE
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The entire pharyngolaryngeal
complex together with upper 5–6
tracheal rings and thyroid and
parathyroid glands is harvested,
leaving the neurovascular pedicle
intact.
The vascular pedicle includes the
superior thyroid arteries, the
internal jugular veins as an
extension of the superior and
middle thyroid veins, the superior
laryngeal nerves, and the recurrent
laryngeal nerves bilaterally.
RECIPIENT
PROCEDURE
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The entire vascular and neural structure of the larynx is delineated.
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An orthotopic position for transferred tissue is created by removing the strap muscles.
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A pouch is created for the pharynx and larynx and pharyngeal anastomosis is established in
the upper part
the upper part of the tracheal stroma is revised, the donor trachea is sutured to this in an
end-to-end manner.
Both superior thyroid arteries are anastomosed to the recipient arteries (end-to-end), or to a
branch of the external carotid arteries (end-to-side).
Donor internal jugular veins are anastomosed to the recipient internal jugular veins (end-toend or end-to-side)
Both superior laryngeal nerves and recurrent laryngeal nerves of the transplanted tissue are
sutured to their recipient matches.
IMMUNOSUPPRESSIVE
PROTOCOL
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Drugs:
1. muromonab-CD3 (5 mg/day)
2. cyclosporine (500 mg/day) / tacrolimus 4 mg twice daily
3. methylprednisolone (50 mg/day, decreasing to 20 mg in 4 days)
4. mycophenolate mofetil (MMF) (1 g twice a day).
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Wide-spectrum antibiotic therapy should be administered for the first 10
postoperative days.
1. Sulfadoxine pyrimethamine - to prevent Pneumocystis carinii pneumonia.
2. CMV prophylaxis - by valganciclovir.
ABDOMINAL WALL
ALLOTRANSPLANTATION
INDICATIONS
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Impossible or high-risk direct abdominal closure in patients undergoing intestinal
allotransplantation.
ABDOMINAL WALL COMPOSITE TISSUE COMPONENT
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The transplanted tissue includes one or both rectus abdominis muscles, overlying
fascia, underlying sheet and abdominal subcutaneous tissue, and skin.
ARTERIAL ANATOMY
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The composite abdominal wall flap is perfused by the inferior epigastric vessels.
These are left in continuity with the common femoral or iliac arteries.
FLAP DESIGN
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The surface area may range from 150 cm–500 cm, based on patient age and size.
DONOR PROCEDURE
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An upper part Mercedes-like incision,
which starts from median sternotomy to
extend to the bilateral subcostal line.
Then a continuous vertical bilateral
incision is made in the lateral borders of
both rectus abdominis muscles.
In the groin region, the two incisions are
connected transversely in the midline.
Both inferior epigastric vessels are
dissected and followed until common
femoral vessels are identified.
The length of the vascular pedicle is
determined based on the desired length
obtained.
RECIPIENT
PROCEDURE
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After reperfusion of the intestinal or multivisceral allograft,
the composite allograft is transferred as a separate tissue.
Vessels of the composite tissue are anastomosed to the
iliac vessels in an end-to-side manner.
The length of the pedicle is adapted in a smooth curve to
prevent uneven tension or kinking.
The transplanted abdominal tissue is incorporated into the
edges of the recipient abdominal wall defect.
IMMUNOSUPPRESSIVE
PROTOCOL
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Induction - Alemtuzumab (0.3 mg/kg) preoperatively,
immediately postoperatively, and on postoperative days 3
and 7.
Maintenance - Tacrolimus with a targeted serum level of
10 μg/L.
In rejection attacks, corticosteroids are used in high doses.
UTERUS
TRANSPLANTATION
INDICATIONS
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Not a lifesaving one and is only intended to improve quality of life.
The ideal recipient :
1. Age 18–45
2. Infertility related to the uterus
3. Desire for uterine transplantation
4. Medical impossibility of having a baby
5. Congenital uterine agenesis
6. Resection of the uterus due to hemorrhage or trauma except for
malignant tumors
7. No history of major trauma or surgery likely to negative affect outcomes
8. Healthy organs and systems
9. Psychosocial stability
10.Good health with no contraindications for immunosuppressive agents
11.Informed concern regarding all adverse effects of immunosuppressive
agents
IMMUNOSUPPRESSIVE
PROTOCOL
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Induction period: Antithymocyte globulin and prednisolone.
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Intraoperatively : Antithymocyte globulin is initiated at a dose of 2.5 mg/kg per day.
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Day of surgery: Prednisolone is started on the, at 1000 mg, and tapered down to 20
mg, 1 week postoperatively.
On day 7: Tacrolimus is started (0.2 mg/kg per day with blood levels between 15
ng/mL and 20 ng/mL),
On day 10: antithymocyte globulin is stopped
Maintenance treatment : prednisolone (20 mg/ day); tacrolimus (blood levels
between 15 ng/mL and 20 ng/mL for the first 3 months, then tapered to 7–10 ng/
mL at 6 months postoperatively) and mycophenolate mofetil (MMF) (2 g/day).
References
1. Flaps & Reconstructive surgery, Wei Mardini, 2nd edition
2. Neligan Plastic surgery, 4th edition, volume 1
3. Grabb and Smith Plastic surgery, 7th edition
4. Hand Transplantation - A Review., Brendan J. MacKay, M.D., Elliot Nacke, M.D., and
Martin Posner, M.D., Bulletin of the Hospital for Joint Diseases 2014;72(1):76-88
5. Face transplant: A revolutionary approach and role of dentist., Tanya Nandkeoliar,
Kaushik Ranjan Deb., Journal of Advanced Clinical & Research Insights (2018), 5,
127–132
6. Quality Improvement in Facial Transplantation: Standard Approach for Novel
Procedures Rami S. Kantar, MD; William J. Rifkin, BA; J. Rodrigo Diaz-Siso, MD; G.
Leslie Bernstein, MPA; Eduardo D. Rodriguez, MD, DDS,. PRS Global Open • 2018
Thank you