Phẫu Thuật Tạo Hình Grabb & Smith’s (Bản Cập Nhật – Kevin C. Chung)

Hyperacute Rejection
This type of rejection is a peracute form with a very rapid onset that occurs within minutes to hours after
transplantation and can destroy the allograft in an equally short period of time. It is mediated through
preexisting antibodies against HLA or ABO antigens which have been acquired as a result of
pretransplant blood transfusions, pregnancies, or previous transplants. These antibodies bind to their
corresponding antigen expressed on endothelial cells of the transplant and subsequently can activate the
coagulation and complement cascade. This leads to the formation of microthrombi, vascular occlusion,
and ultimately necrosis of the allograft. However, blood type matching, HLA typing of donor and
recipient, and pretransplant routine clinical cross-matching, whereby preformed anti-HLA antibodies are
screened for have virtually eliminated hyperactive rejection episodes in both solid organ as well as
reconstructive transplantation.
mebooksfree.net

Acute Rejection
Acute rejection episodes typically manifest within a period of days or weeks after transplant but can
occur also at much later time points (months or years) if the immune system is awakened either by
infection or by a significant reduction in immunosuppression. The primary mediator of acute rejection
episodes are effector T cells that infiltrate the graft and lead to inflammatory damage and parenchymal
necrosis. About 30% of all cases of acute rejection, however, are mediated by antibodies (donor-specific
IgG antibodies) and are referred to as humoral or vascular rejection episodes. These antibodies bind to
endothelial cells and activate the complement cascade which in turn leads to deposition of complement
factors C3d and C4d that trigger endothelial inflammation and cellular infiltration resulting in vascular
damage and occlusion. Given the advances in modern immunosuppression, acute rejection episodes for
most type of organ transplants are ranging between 3% and 10% and can usually be successfully reversed
with either steroid bolus therapy, antibody treatment (thymoglobulin or alemtuzumab), or with
plasmapheresis and high-dose IVIG.
mebooksfree.net

Chronic Rejection
Chronic rejection is the leading cause affecting long-term outcomes after transplantation. This type of
rejection is a slow form of rejection that primarily targets the graft vasculature (concentric vascular
stenosis also referred to as graft vasculopathy) and causes graft fibroses. The onset of chronic rejection is
usually beyond 1 year post transplant and most often progresses gradually over several years, eventually
leading to a gradual decline in organ function and ultimately graft loss. Mechanistically both humoral as
well as cellular responses, including DTH reactions and proinflammatory cytokines (IFN-g, fibroblast
growth factor, or TGF-b), are involved in the onset and progression of chronic rejection. In addition,
residual scarring from episodes of acute rejection contributes to chronic graft failure. Alloreactive T cells
are infiltrating the transplant and release cytokines and chemokines such as CCL5 which in turn recruit
monocytes that differentiate into macrophages. The second phase of this chronic inflammatory process is
dominated by macrophages which release IL-1, TNF-a, and MCP-1 and thereby perpetuate the chronic
inflammatory state, ultimately leading to graft fibrosis and sclerosis and loss of function. In addition to
these antigen-specific mechanisms, antigen-independent factors such as ischemia-reperfusion injury,
chronic toxicity of maintenance immunosuppression, and infectious complications such CMV can
contribute to the development of chronic rejection and graft vasculopathy.
mebooksfree.net

Immunosuppression
In addition to advances in surgical techniques, the development of potent and targeted
immunosuppressive agents has probably contributed the most to the success story of organ
transplantation. 29,32,33 Today, there is a whole armamentarium of pharmacological agents available that
can be used to prevent and control allograft rejection 32 (Figure 8.3; Table 8.1). Based on their mode of
action, there are six major categories of immunosuppressive drugs: induction agents (e.g., mono- and
polyclonal antibodies), antiproliferative agents, CNIs, mTOR inhibitors, corticosteroids, and biologic
agents.
mebooksfree.net

FIGURE 8.3 Targets of immunosuppressants during T cell activation. Immunosuppressive medications interrupt T cell
activation at various pathways. CsA and tacrolimus interrupt the TCR signaling cascade by blocking calcineurin activation, the
latter by interaction with FK-binding proteins. RAPA blocks mTOR signaling from both IL-2 receptor activation and from TCR
coreceptors interrupting the second signal pathway. Steroids alter gene transcription by modulating the effects of transcription
factors including several necessary for T cell activation. AZT and MMF inhibit the production of nucleotides in lymphocytes
blocking the cell cycle and proliferation. APC, antigen-presenting cells; AZT, azathioprine; MMF, mycophenolate mofetil; TCR, T
mebooksfree.net

cell receptor.
TABLE 8.1
Immunosuppressive Agents in Current Use
Class of Drug
Agents
Mode of Action
Main Adverse Effects
Induction agents
Antithymocyte globulin (ATG),
alemtuzumab
Antibody-dependent cell-
mediated cytotoxicity
Cytokine release syndrome, leukopenia, anemia,
bleeding, hypertension
Antiproliferative
agents
Azathioprine
Mycophenolate mofetil (MMF)
Blockade of DNA
synthesis and replication
Gastrointestinal (GI) complaints, diarrhea, viral
reactivation, myelosuppression/leukopenia
Calcineurin
inhibitors
Cyclosporine A (CsA)
Tacrolimus
Inhibition of IL-2 gene
transcription
Nephrotoxicity, hypertension, hyperglycemia,
tremor, hirsutism, gingival hyperplasia, acne
mTOR
inhibitors
Rapamycin
Everolimus
Inhibits signal
transduction
Hyperlipidemia, wound-healing problems,
thrombocytopenia, anemia, peripheral edema,
ulceration of oral mucosa
Steroids
Methylprednisolone
Prednisolone
Inhibition of multiple
transcription factors anti-
inflammatory
Diabetes, fluid retention, weight gain,
dyslipidemia, hip necrosis, acne, glaucoma
Biologics
Cytotoxic T-lymphocyte–associated
antigen-4 immunoglobulin (CTLA4-
Ig) (Belatacept)
Blocks costimulatory
pathway B7-CD28
Cytokine release syndrome, fever, leukopenia,
anemia
Basiliximab
IL-2 receptor antagonism
Tremor, bleeding, fever, chills
Rituximab
CD20 binding on B cells
Infusion reaction, cytokine release syndrome
Infliximab
TNF-a inhibition
Infection, tuberculosis reactivation, drug-induced
lupus
mebooksfree.net

Induction Agents
Polyclonal antithymocyte globulin or antilymphocyte globulin reagents can be distinguished from each
other by the cells used for the immunization and the animal species from which they are produced. The
mechanism by which antithymocyte globulins achieve their immunosuppressive action is by peripheral
blood lymphocyte depletion through antibody-dependent cell-mediated cytotoxicity or Fas-dependent
apoptosis. Alemtuzumab (Campath-1H) is an anti-CD52 monoclonal antibody that similarly depletes T
cells, B cells, and NK cells by antibody-dependent cellular-mediated lysis. Basiliximab is a recombinant
monoclonal antibody that binds to and blocks the IL-2 receptor on the surface of T cells. Induction
therapy with lymphodepleting agents has allowed for a significant reduction in the incidence of acute
allograft rejection and to a diminution of maintenance immunosuppression to promote CNI reduction
and steroid avoidance or withdrawal.
mebooksfree.net

Antiproliferative Agents
Cytotoxic/antiproliferative drugs include cyclophosphamide, methotrexate, AZT, and MMF. These agents
interfere with DNA replication and arrest proliferating alloreactive lymphocytes. Earlier nonspecific
antiproliferative agents such as AZT had many side effects and unwanted toxicities. MMF has replaced
these agents in many protocols due to its ability to selectively block purine synthesis in T and B cells,
which dramatically improves the side effect profile.
mebooksfree.net

Calcineurin Inhibitors
Cyclosporine A (CsA) and tacrolimus both inhibit the signaling pathways of T cell activation by
interfering with calcineurin activation and IL-2 gene transcription. CsA is a metabolic extract from the
fungus Tolypocladium inflatum Gams first described in 1976. Its discovery revolutionized the field of solid
organ transplantation by significantly increasing survival of kidney, heart, and liver allografts. CsA has
been shown to prolong limb allograft survival in various experimental animal models and thereby
significantly encouraged to pursue clinical VCA in the 80s and 90s. Tacrolimus is a macrolide lactone
antibiotic isolated from soil fungus and also inhibits the calcineurin/IL-2 pathway of T cell activation,
although at a different point in the pathway from cyclosporine. It has a favorable side effect profile as
compared with CsA and less transplant-associated malignancy potential, although it has significant
nephrotoxicity when used for long periods of time. Tacrolimus has replaced cyclosporine in many
protocols in solid organ and has been the backbone of all the clinical reconstructive transplantation
treatment regimens. A beneficial side effect of immunosuppression with tacrolimus in the setting of VCA
is its dose-dependent acceleration of axonal regeneration, which promotes functional recovery after
reconstructive transplantation.
mebooksfree.net

mTOR Inhibitors
The unfavorable toxicity profile of CNIs, in particular its considerably high nephrotoxicity, has led some
centers to switch to the mTOR inhibitor rapamycin (sirolimus, everolimus). Rapamycin and other mTOR
inhibitors act downstream of signal 3, inhibiting the response to IL-2 (as well as IL-4, IL-7, IL-12, and IL-
15), thereby effectively inhibiting T cell proliferation. Rapamycin is a very attractive alternative to CNIs,
as it has a significantly different side effect profile in particular with regard to its nephrotoxicity and
having antiproliferative and antineoplastic properties. It does, however, suffer the drawback of having
profound negative effects on wound healing that may preclude its use in the early postoperative period.
mebooksfree.net

Corticosteroids
One of the first available immunosuppressants for transplantation was steroids with broad anti-
inflammatory actions (i.e., prednisone, prednisolone). These medications inhibit activation of several
transcription factors, thus modifying gene expression, inhibiting cellular activation, and cytokine
production. Prednisolone was one of the first pharmacological agents used in allogeneic organ
transplantation. Despite the well-known side effects of long-term use, steroids are still widely utilized
today in combination with other immunosuppressive agents in most solid organ and VCA protocols.
However, steroid avoidance, minimization, and withdrawal had been common practice even from the
beginning of transplantation. Short courses of high-dose bolused steroids continue to be the frontline
treatment for acute rejection episodes in all types of transplantation.
mebooksfree.net

Biologic Agents
Biologic agents such as cytotoxic T-lymphocyte–associated antigen-4 immunoglobulin (CTLA4-Ig) (e.g.,
abatacept, belatacept), which block T cell costimulation, were developed to overcome the limitations of
conventional immunosuppressants and represent a new paradigm in immunosuppression—biological
therapy for maintenance immunosuppression devoid of the toxicities associated with CNIs. CTLA4-Ig is
an engineered fusion protein comprised of the extracellular human domain of CTLA4 and the hinge CH2
and CH3 domains of a human or mouse IgG1 that binds to B7 molecules with high affinity thus
preventing CD28-B7 engagement and leading to partial T cell activation and T cell anergy. Multiple
groups have demonstrated potent immunosuppressive properties of CTLA4-Ig in vivo using rodent
models of transplantation and autoimmunity. Recently a novel mutant of CTLA4-Ig (LEA29Y, belatacept)
with increased binding affinity to B7 has been generated and successfully introduced into human trials
with favorable results. These phase II and III studies in renal transplantation demonstrated that
belatacept-based immunosuppression is an effective alternative to CNIs. 34
Other biologic agents used for immunosuppression in transplantation include rituximab, a chimeric
murine/human monoclonal antibody that reacts with the CD20 antigen on B cells, infliximab a high-
molecular-weight (149 kDa) chimeric monoclonal antibody against TNF-a, CFZ533 a new, fully human,
Fc-silenced, nondepleting, IgG1 mAb preventing CD40 pathway signaling and activation of CD40 + cell
types, and the IL-2 receptor antagonists also referred to as anti-CD25 monoclonal antibodies, basiliximab
and daclizumab. 32
Despite this plethora of immunosuppressive agents, there is currently no standard immunosuppressive
protocol established for either solid organ or reconstructive transplantation.
The current immunosuppressive protocols applied to hand, upper extremity, and face transplantation are
extrapolated from various different regimens and protocols used in solid organ transplantation. The
overall amount of immunosuppression required to ensure graft survival is comparable or even slightly
higher than it is for kidney transplantation.
mebooksfree.net

Transplantation Tolerance
Sir Peter Medawar’s seminal experiments with skin transplantation laid the foundation for Transplant
Immunology; subsequent experimentation by his group in animal models led to the first documentation
of acquired immune tolerance. This phenomenon was defined as a state of donor-specific hyporesponsiveness, in
the absence of immunosuppression, while maintaining adequate immune responses to third party antigens. 12
This definition is still valid today and implies that a state of tolerance must coexist with general immune
competence, including normal immune responses to pathogens and cancer risks no different than the
general population. During development, one of the critical functions of the immune system is to prevent
responses directed toward self-antigens and thereby preventing autoimmune disease. This vital ability of
the immune system to distinguish between self- and foreign antigens is controlled by two main
mechanisms referred to as central and peripheral tolerance. Central tolerance is facilitated in the thymus
whereas peripheral tolerance is induced in extrathymic secondary lymphoid tissues. The mechanism of T
cell tolerance in the thymus is based on the deletion of self or alloreactive T cells upon interaction with
bone marrow–derived APCs. In general, during T cell development, the majority of T cells found in the
thymus have undesirable reactivities and are therefore deleted via negative selection. T cells that
recognize foreign antigen in the context of self-MHC are positively selected and allowed to circulate in
the peripheral blood. Another widely researched approach for the induction of tolerance is the use of
hematopoietic stem cell transplantations to induce mixed chimerism. 35
Mixed chimerism refers to a state in which donor and recipient cells coexist within the recipient. This
state can be established in clinical practice via donor hematopoietic stem cells, which are mobilized from
the donor bone marrow, collected from peripheral blood, and then administered to the recipient. Donor
HSCs engraft into the recipient’s bone marrow and, in conjunction with recipient HSCs, ensure the
constant production of myeloid and lymphoid cell lineages: the recipient’s immune system is now
composed by cells both of donor and of recipient origin. Immune tolerance was achieved via mixed
chimerism in a variety of animal models; clonal deletion was demonstrated as one of the primary
mechanism in this process. In humans, mixed chimerism was achieved, in the vast majority of cases, only
as a transient state; however, in certain patients, immune tolerance persists long after the loss of mixed
chimerism: this indicates that mechanisms other than clonal deletion might be at play. A remaining major
challenge to achieving tolerance routinely through the induction of mixed chimerism is the need for
intense preconditioning regimens with considerable toxicities. 35,36
Peripheral tolerance in contrast is maintained by a number of mechanisms, including clonal deletion,
anergy (e.g., nonresponsiveness), and suppression/regulation. The induction of T cell anergy has been
demonstrated by blockade of costimulatory signals (signal 2) using monoclonal antibodies during T cell
activation (see Figure 8.2). Anergic T cells are incapable of producing IL-2 and are unresponsive to repeat
antigen stimulation unless exogenous IL-2 is added. The induction of T regulatory/suppressor cells is
another mechanism to induce T cell tolerance specific to donor antigens. T regulatory cells
(CD4+CD25+Foxp3+ T regs) play a key role in the maintenance of tolerance to both self- and foreign
antigens. 37 Furthermore, studies in recent years have demonstrated the potential role for particular
subtypes of DCs such as plasmacytoid to promote and maintain peripheral tolerance to transplantation
antigens. Another mechanism leading to peripheral tolerance is clonal exhaustion and deletion, which is
due to chronic or overwhelming antigen 
 exposure/stimulation under suboptimal conditions.
mebooksfree.net

Transplantation Applications in Plastic Surgery
Skin
Skin allografts are the most commonly performed human allotransplant and were the basis of the first
transplantation research. Pioneering experiments by Giuseppe Baronio, as outlined above, on auto- and
allografts in sheep laid the groundwork for research in the fields of both skin grafting and transplant
immunology. 8 The most frequent clinical use for skin allografts is in the treatment of extensive burns.
The ability to place temporary skin grafts without jeopardizing limited autogenous donor sites in these
patients has resulted in dramatic improvements in survival of high total body surface area burn wounds.
In some patients who are immunosuppressed either through medications or through severe illness, skin
allografts have been shown to be tolerated with continued immunosuppression. Anecdotal reports of
patients who have undergone slow withdrawal of immunosuppression have not required regrafting
either through permanent tolerance of the graft or more likely through slow substitution of the allograft
with recipient cells. 38 Future research developments that enable prolonged graft survival in the absence
of immunosuppression would precipitate a significant paradigm shift in the treatment of severe wounds
and burns.
mebooksfree.net

Skin Xenograft
Porcine xenograft has been used as a temporary dressing for large burns. It is applied with a technique
similar to that used for human allograft, with seeding of autologous grafts beneath it. The application of
xenogeneic dermis has also been found valuable in preparing a wound for subsequent grafting by
stimulation of granulation tissue formation. Xenogeneic tissue has limited uses in skin grafting at present,
and its cellular components are susceptible to hyperacute rejection typical of all xenograft materials.
mebooksfree.net

Bone Allograft
Reconstruction of large bony defects in the axial and peripheral skeleton with nonvascularized allogeneic
bone has been widely practiced. Well-organized tissue banks and improved methods of bone sterilization
and preservation have made this possible. Very few of the donor cells, if any, in the nonvascularized bone
allograft survive. These donor cells express antigens similar to other allogeneic tissues and are susceptible
to rejection. The remaining bone acts as a scaffold for ingrowth of recipient mesenchymal stem cells
(osteocyte precursors), which repopulates the donor by creeping substitution. Although technically an
allogeneic tissue transplant, these grafts are essentially totally replaced by recipient cells once the healing
process is complete and no immunosuppression is given. Owing to slow union, long-term fixation is
required of bone allograft, which is prone to stress fracture and loosening of fixation hardware. In studies
of retrieved human allografts, however, union was seen at the graft-host interface.
Vascularized bone allograft on the other hand contains living donor cells and is susceptible to
immunologic rejection. The humoral and cellular response generated to transplanted bone was found to
be similar in intensity and timing as that generated by other vascularized allogeneic limb tissues such as
the skin and muscle. Although individual bone cells express antigens, the predominant antigenic
stimulus in a bone allograft is thought to be derived from the marrow. Removal of bone marrow by
irradiation or replacement with recipient marrow has been shown experimentally to prolong allograft
survival. Like any other allogeneic tissue, this rejection process can be ameliorated with
immunosuppression, and long-term survival of orthotopic vascularized skeletal allograft has been
achieved in animal models. However, the adverse effects of prolonged immunosuppression required for
survival of a vascularized bone allograft preclude its clinical application currently as an autologous
sources of vascularized bone. Non-vascularized allografts are usually sufficient to reconstruct most
simple bone defects.
mebooksfree.net

Cartilage Allograft
Cartilage is composed of chondrocytes within lacunae dispersed throughout a water-laden matrix. The
matrix is composed predominantly of proteoglycans and type II collagen. Water is important as cartilage
has no intrinsic blood supply and relies on diffusion of nutrients and oxygen through this matrix. The
combination of water and proteoglycans imparts the characteristic of viscoelasticity depending on the
relative concentrations of both elements. The variable water content in the matrix causes a balanced
tension within it and helps maintain its three-dimensional shape. The viscoelastic property of the matrix
confers memory such that cartilage returns to its original shape after deformation. Surgical manipulation
or scoring disrupts this equilibrium. In contrast to osteocytes, chondrocytes have little reparative ability
and heal by forming fibrous scar tissue. There are histologically three types of cartilage: hyaline, elastic,
and fibrocartilage. Chondrocytes express HLA antigens on their surface and are thus immunogenic in
isolation. Cartilage, however, is immunologically privileged owing to the shielding of chondrocytes by its
matrix, which is only weakly antigenic. Surgical scoring or dicing of cartilage allograft with resultant
exposure of allogeneic cells has been shown to hasten cartilage resorption. Cartilage allografts have been
used successfully for similar applications as autologous cartilage. Allogeneic cartilage can be either
preserved or fresh. Preserved cartilage has the advantage of a more abundant supply and decreased risk
of infection in comparison to fresh cartilage. Although immunologically privileged, cartilage allografts
are still susceptible to loss of volume through resorption. Whether this is due to immunologic rejection or
lack of viable cells following preservation is a matter for debate.
mebooksfree.net

Cartilage Xenograft
Some authors have advocated the use of bovine-derived cartilage xenografts. However, both
chondrocytes and matrix are subject to xenogeneic mechanisms of rejection with a generally poorer
outcome in comparison to autologous or allogeneic cartilage grafts. Attempts to modify these xenogeneic
responses by altering the graft’s immunologic stereotactic structure have been reported as being
beneficial.
mebooksfree.net

Nerve Allograft
The best clinical outcome following nerve transection is achieved with primary repair. More extensive
injuries or a delay in repair may result in a nerve gap following debridement of damaged nerves, and a
nerve graft may be necessary to achieve neurorrhaphy without tension. The nerve graft undergoes the
same degenerative process as in the distal nerve after division. The myelin sheath remains with Schwann
cells that act as a biological conduit for the regenerating axons. Vascularized nerve grafts are theoretically
advantageous particularly in scarred beds. Other conduits used as nerve grafts have included autologous
vein, silicone tubes seeded with Schwann cells, and freeze-fractured autologous muscle. Autologous
nerve grafts with acceptable donor site morbidity are limited, and extensive nerve reconstruction may
require other sources such as nerve allografts. Immunological rejection of nerve allograft can be
ameliorated experimentally with immunosuppressive drugs, and axons were found to traverse the
allogeneic nerve graft in rodents. A similar result has also been demonstrated in primates.
Immunosuppression was necessary during axonal regeneration but could be terminated afterward in
some studies with satisfactory nerve functions. In the only clinical experience, Mackinnon reported return
of motor and sensory functions in the upper or lower limbs of six out of seven patients following nerve
allograft reconstruction. 39
mebooksfree.net

Reconstructive Transplantation
Reconstructive transplantation or, as it is also referred to, vascularized composite allotransplantation
(VCA) has become a valid therapeutic and restorative option for patients with severe tissue defects not
amendable to conventional reconstruction. 3–5,20,21 Significant advances in both basic science and
translational research related to transplant immunology paired with the development of more potent and
targeted immunosuppressive agents over the past 2 decades as well as highly encouraging functional and
immunological clinical outcomes have led VCA to transition from an experimental and sometimes
controversial procedure to an accepted and rapidly expanding field with great promise.
mebooksfree.net

Upper Extremity Transplantation
It has been well documented that reconstructive transplants can be maintained on conventional triple
drug immunosuppression at levels similar to that used in solid organ transplantation. 40,41 Patients after
upper extremity transplantation have functional motor and sensory recovery similar to that seen with
replantation. Since the beginning of the modern era of hand transplantation in 1998, there have been over
140 hand and upper extremity transplants performed worldwide in centers across the United States,
Europe, and Asia. In general, and as reported in the International Registry on Hand and Composite
Tissue Transplantation, results have been highly satisfactory with very few grafts lost, on average good
hand function, and relatively few major side effects and complications. 3,5,18 Immunosuppressive side
effects included predominately opportunistic infection (i.e., CMV), metabolic complications such as
diabetes and hypertension, nephrotoxicity (requiring renal transplantation in some cases), avascular
necrosis of the hip, and the occurrence of posttransplant malignancy such as PTLD. Although the
risk/benefit equation of placing a patient on long-term immunosuppressive medications for a
nonlifesaving type of transplant must always be considered, advances such as minimization protocols
using donor bone marrow infusion and monotherapy maintenance have been successfully developed in
large animal models and are currently being studied in humans. 6,7,42–44 Such innovative alternative
protocols are anticipated to favorably alter this balance in the future. Thus, the consensus among many
patients is that VCA delivers considerable improvements in function, independence, and quality of life.
Such functional gains allow these patients to perform a variety of daily activities such as eating, writing,
driving, grasping, shaving, while, in some cases, dramatically improving their social life and enabling
them to return to work full time (Figure 8.4). As a consequence, upper extremity transplantation is
increasingly being seen as another alternative in the reconstructive armamentarium used to treat patients
with upper extremity amputations. Hand and upper extremity transplantation has demonstrated the
ability to restore the structure and function of the hand in a way not possible with any other
reconstructive technique by truly replacing like with like (Figure 8.5). Hence, it appears that reconstructive
transplantation will continue to play an increasing role in the treatment of patients with upper limb
amputations. However, balancing the risk/benefit ratio in particular the risks of and toxicities of systemic
immunosuppression against all the improving in function, patient autonomy, and quality of life will
remain the prime task of this field for the foreseeable future.
mebooksfree.net

FIGURE 8.4 Functional outcome after bilateral upper extremity transplantation. Demonstration of excellent functional outcome
in a patient more than 8 years after bilateral upper extremity transplantation (left side at wrist level and right side above elbow at
mid humerus level).
mebooksfree.net

FIGURE 8.5 Upper extremity transplantation. Schematic diagram showing the technique of mid-forearm hand transplantation.
All structures are prepared and labeled prior to transplantation and osseous fixation. Note the opposing, interdigitating skin flap
design.
mebooksfree.net

Face Transplantation
No other area of reconstructive transplantation captures the imagination of patients, clinicians, and the
public like face transplantation. Especially because human beings’ perception of self is intimately tied to
one’s facial appearance. In addition, the face provides information not only about self-identity, but also
age, gender, and ethnicity of an individual and thus affects social interactions, integration, and perception
of body image. For patients with severe and devastating injuries to the craniofacial skeleton and soft
tissues of the face, there is currently no other acceptable, effective restorative option using standard
reconstructive techniques. For these patients, transplantation of allogeneic cadaveric facial structures has
shown to be the only viable option of regaining normal facial appearance and being able to reintegrate
into society in a meaningful way.
Since the first partial face transplantation has been carried out in 2005 by Drs. Dubernard and
Devauchelle in France, a total of 40 cases of craniofacial transplantation have been performed worldwide
and thereby shown technical feasibility and promising immunological, functional, psychological, and
aesthetic results. 20,21,45 Transplanted grafts have consisted of just soft tissue (the nose and lips) up to and
including all facial soft tissue and portions of facial bones and the tongue (entire face, maxilla, anterior
portion of the mandible, and tongue). Indications for these procedures have included ballistic trauma
sustained by military personnel and civilians, animal bites, tumor resection, neurofibromatosis, and
burns. All of the facial allografts have included either portions of the orbicularis oris or oculi; loss of the
sphincter function of the mimetic muscles of the face is generally considered to be one of the indications
for facial transplantation. In general, patients have been maintained on immunosuppression similar to
that used for upper extremity or solid organ transplantation with all patients receiving induction therapy
followed by triple drug immunosuppression. Tacrolimus has been the cornerstone of nearly the majority
of immunosuppression protocols used in face transplantation with target trough levels of 10 to 15 ng/mL
for the first 6 months with most patients subsequently lowering to a maintenance level of 8 to 10 ng/mL.
Corticosteroids have been safely tapered after a few months, with complete withdrawal possible within a
year in some cases, depending on the immunosuppression regimen. Overall, immunological and
functional patient outcomes have been highly satisfactory. All patients receiving facial transplantation
have dramatically improved their aesthetic appearance allowing them to be reintegrated into society and
have a normal and productive social life. However, functional outcomes are difficult to quantify
uniformly owing to the complexity of facial functions and the wide range of extend of injures across face
transplantation recipients. All patients for whom outcomes have been reported in the literature have
developed nearly normal sensory function with return of two-point discrimination and temperature
differentiation between 3 and 8 months after transplantation. Motor recovery has been slightly slower but
all patients have recovered some degree of motor function allowing for oral competence, the ability to
breathe, eat, taste, smell, and speak, and for facial expression. Typical motor recovery is detectable as
early as 6 to 8 months post transplant with maximum recovery around 18 months after transplant.
Unfortunately, there have now been first cases of chronic rejection reported for face transplantation
which resulted in subsequent graft loss, including the very first French patient. In addition, as of the time
of this writing and to the best of the author’s knowledge, there have been five mortalities associated with
facial transplantation. Two perioperative deaths occurred when combined VCA face + upper extremity
was attempted. One case of mortal tumor recurrence in an HIV + recipient, one case of de novo
posttransplant lung cancer, and one case due to noncompliance, resulting in an 86% patient survival rate
after face transplantation. Other known risks include the development of systemic infections, metabolic
complications, or the chance to develop cancer due to long-term immunosuppression. 20,21 Although
technically highly demanding and the potential for serious and eventually life-threatening complications,
facial transplantation has the unique potential to restore patients to normalcy and save them from social
mebooksfree.net

death. There is a clear indication that for carefully selected patients, facial transplantation offers a
procedure that, although not lifesaving, is potentially life restoring.
mebooksfree.net

Other Areas and Latest Developments in Reconstructive
Transplantation
Developments in reconstructive transplantation have clearly been led by upper extremity and facial
transplantation. However, there have been smaller series of patients treated with transplantation of
several other composite structures including vascularized knee joints, lower extremities, trachea, larynx,
abdominal wall, and reproductive organs. With the exception of vascularized knee joints (which have
failed in five of the six patients attempted owing to chronic vascular complications), reconstruction with
these varied types of transplants has met with some qualified success. Although these less common types
of transplants continue to be highly experimental, they demonstrate the possibilities that reconstructive
transplantation offers. Traditional plastic surgery techniques are unable to restore complex tissues and
anatomical structures with the fidelity equal to that of reconstructive transplantation as evidenced by
recipients’ functional and aesthetic outcomes.
mebooksfree.net

Uterus Transplantation
Given the highly encouraging outcomes seen in upper extremity and face transplantation, indications for
VCA to reconstruct other devastating tissue defects or organ losses are rapidly expanding. One such
example is uterus transplantation, which has now emerged as the first therapy for women with absolute
uterine factor infertility, who have traditionally been regarded as unconditionally infertile. Two isolated
cases of uterine transplantation were reported in 2000 and 2011 by teams in Saudi Arabia and in Turkey.
Although both surgeries were initially successful, the first patient lost the graft at 3 months due to uterine
artery thrombosis and the second patient suffered two early miscarriages after embryo transfer. In 2014, a
team in Sweden reported the first birth of a child to a uterine transplant recipient, who had undergone
single embryo transfer 1 year after transplantation. 46 Several more successful live births have been
reported since then from the nine women who have entered this initial Swedish trial. The field of uterus
transplantation is expanding at a staggering pace, with active centers being established all around the
world. At least 10 new clinical trials have just started or are in the process to start as of 2018.
Of note, uterine transplantation represents the first ephemeral type of transplantation. 47 As hysterectomy
can be performed after successful pregnancy, concerns about long-term side effects from
immunosuppression would not apply. Although uterus transplantation has been shown to be a highly
effective and successful treatment for absolute uterine factor infertility, it also raises a series of ethical
questions. For instance, Huet et al. reviewed potential candidates for transplantation: some presented
with complete androgen insensitivity syndrome. 48 These patients are phenotypically and psychosocially
female but genetically male; the question that has been posed was should they be considered eligible?
This question can further be extended to transgender individuals and will require further sensitive
discussion.
mebooksfree.net

Penile Transplantation
Penile transplantation is another emerging option for patients with severe genital defects not amenable to
traditional reconstructive techniques. 49 Patients with penile defects frequently suffer from debilitating
physical and psychosocial impairments, including inability to have sexual intercourse or urinate while
standing, feelings of emasculation, disruption of interpersonal relationships, and profound loss of quality
of life. Although traditional phalloplastic reconstruction can produce satisfactory outcomes in many
cases, it is limited by a high rate of complications involving prosthesis extrusion and urinary strictures
and fistulae. Furthermore, there is a growing cohort of patients with traumatic penile loss and
concomitant extremity injuries who are not candidates for autogenous reconstruction because they lack
adequate donor sites. For patients who have either failed autogenous reconstruction or are not
appropriate candidates, penile allotransplantation may offer a viable alternative.
The first penile transplant was performed in 2006 by a team in Guangzhou, China: a patient who
sustained traumatic amputation received a transplant from a deceased donor. The surgery involved
microsurgical anastomoses of the urethra, deep and superficial dorsal veins, dorsal arteries, and dorsal
nerves, as well as of the corpus spongiosum and corpora cavernosa. Despite encouraging early results,
the graft was explanted 2 weeks later at the recipient’s request because of severe psychological problem of the
patient and his wife. The second and third cases were performed in 2014 and 2016 in South Africa and in
the United States, respectively. The South African patient was a 21-year-old man who suffered partial loss
of his penis as a complication of ritual circumcision. 50 The Boston patient was a 64-year-old man who,
4 years earlier, underwent penectomy to treat penile squamous cell carcinoma. 51 In March 2018, a team at
Johns Hopkins University performed the world’s first entire penis and scrotum transplantation in a
wounded warrior who had sustained a devastating injury several years earlier from an improvised
explosive device while serving in Afghanistan. These three successful transplants provide proof of
principle that penile transplantation is technically feasible with encouraging functional outcomes
(urination, erogenous sensation, and erectile function) and thus constitutes a promising option for repair
of extensive urogenital tissue loss. Given that penile transplantation is still in its infancy, implementing a
successful penile transplantation program will require development of de novo protocols that take into
account a number of important immunological, diagnostic, logistical, procedural, and ethical
considerations. To maximize the utility and viability of penile transplantation as a reconstructive option,
careful attention must be given to these important aspects pertaining to penile transplantation.
mebooksfree.net

Novel Technologies and Future Outlook
Novel technologies such as tissue engineering and regenerative medicine will play a significant role in
the future development of reconstructive transplantation. Regenerated nerves, vessels, bone, etc., will
further expand indications to full arm and lower extremity and to eventually perform transplants in a
more rapid, safer, and successful fashion. Along those lines, three-dimensional bioprinting could help to
further optimize outcomes by enhancing the graft or advancing rehabilitation strategies and approaches
currently in use for upper extremity transplantation. Ultimately, bioengineering technologies, which are
currently developed in advanced prosthetic programs, could further help to improve outcomes and
efforts and even augment or enhance function after VCA in the future. As clinical experience with these
techniques is accumulated and immunosuppressive and immunomodulatory protocols are optimized,
the risk-benefit ratio of reconstructive transplantation will continue to shift in favor of these procedures,
making these techniques an increasingly available and important part of plastic surgeons’ reconstructive
options for treating these crippling defects.
mebooksfree.net

Questions
1. Which of the following immunosuppressive agents belongs to the class of CNIs?
a. Rapamycin
b. Belatacept
c. Tacrolimus
d. Thymoglobulin
2. The initiation of an alloimmune response is a well-orchestrated and choreographed interplay of
various different players of the immune system. Alloreactive T cells require three distinct signals for
full activation. What constitutes signal 2?
a. The NF-κB pathway
b. Costimulatory pathways (B7-CD28, CD40-CD154)
c. The interaction of MHC and TCR
d. None of the above
3. What cell type is predominantly driving an acute alloimmune response?
a. B cells
b. Macrophages
c. T regulatory cells
d. CD4+ and CD8+ T cells
e. DCs
4. Most upper extremity and face transplant patients experience episodes of acute rejection during
the first year post transplant. In which tissue component of the graft does acute rejection
predominately manifest in VCA?
a. Muscle
b. Vasculature
c. Bone
d. Skin
e. Nerves
5. Technical limitations with regard to the feasibility of performing vascular anastomosis have
hampered the development of organ transplantation for centuries. This obstacle was finally
overcome when which surgeon introduced his vascular anastomosis technique?
a. Joseph E. Murray
b. Alexis Carrel
c. Giuseppe Baronio
d. Gaspare Tagliacozzi
e. Thomas E. Starzl
1. Answer: c. Tacrolimus and CsA are CNIs and are the most widely used maintenance
immunosuppressive agents for both solid organ and reconstructive transplantation. Both agents
inhibit the calcineurin/IL-2 pathway of T cell activation and due to their potent immunosuppressive
activity have revolutionized the field of solid organ transplantation by significantly increasing
survival of kidney, heart, and liver allografts in the 80s and 90s. Belatacept is a biologic agent
(monoclonal antibody CTLA-Ig) and inhibits the costimulatory signal B7-CD28. Rapamycin is an
mTOR inhibitor and acts downstream of signal 3 inhibiting the response to IL-2. Thymoglobulin is a
polyclonal antithymocyte antibody primarily used as induction agent to deplete peripheral blood
lymphocytes through antibody-dependent cell-mediated cytotoxicity.
2. Answer: b. In addition to signal 1, APCs provide so called costimulatory signals to fully active T
mebooksfree.net

cells. These costimulatory signals are also referred to as signal 2 during T cell activation. Two of the
best-characterized costimulatory signals/pathways in transplantation are the B7/CD28 and the
CD40/CD154 pathways. The NF-κB pathway is activated as part of the intracellular signal
transduction cascade referred to as signal 3 during T cell activation. Within the secondary lymph
nodes, T cells encounter the MHC alloantigen that is expressed on the surface of the DCs with their
specific TTCRs combined with the CD3 complex that facilitates signal transduction. This interaction
of MHC, TCR, and CD3 complex is referred to as signal 1.
3. Answer: d. The primary mediators of acute rejection episodes are CD4+ and CD8+ T cells that
upon activation infiltrate the graft and lead to inflammatory damage and parenchymal tissue
necrosis. B cells are involved in the production of donor-specific antibodies and late antibody-
mediated rejection. These antibodies bind to endothelial cells and activate the complement cascade,
which in turn leads to deposition of complement factors C3d and C4d that trigger endothelial
inflammation and cellular infiltration resulting in vascular damage and occlusion. T regulatory cells
(CD4+CD25+Foxp3+ T regs) play a key role in the maintenance of peripheral tolerance to both self-
and foreign antigens. DCs are key players in the initiation of an alloimmune response and serve as
APCs to T cells but do not have effector function. Macrophages contribute to both the innate and
acquired arms of the alloimmune response and play pluripotent roles during allograft rejection. They
can induce allograft injury but, conversely, can also promote tissue repair in ischemia-reperfusion
injury and acute rejection.
4. Answer: d. Acute rejection remains a considerable challenge in reconstructive transplantation.
Notably, 85% of all hand, upper extremity, and face allograft recipients have experienced at least one
episode of acute rejection within the first year after transplant, and as much as 56% experienced
multiple episodes. The skin is the most antigenic component of a vascularized composite allograft
and thus represents the primary manifestation of acute rejection. The high antigenicity of the skin
can in part be related to the high proportion of potent APCs (Langerhans cells) and keratinocytes
which express MHC I constitutively and MHC II, ICAM-I, and proinflammatory cytokines upon
stimulation. Skin rejection usually manifests clinically with maculopapular skin lesions restricted to
small areas or spread over the whole allograft, varying in color and location and presenting with or
without edema. While skin rejection is most frequently observed after human hand and face
allotransplantation, an immune response toward tissues other than the skin such as muscle, nerves,
and bone has been documented, however, to a much lesser extend and usually only during very
advanced stages of untreated rejection. More recent findings, furthermore, indicate that also the
vasculature of the graft may be affected and proliferation of the myointima can occur as a sign of
chronic rejection.
5. Answer: b. The obstacle of vascular anastomosis was overcome in 1902 when Alexis Carrel
introduced his vascular anastomosis technique, which unlocked a continuum of research in
experimental organ transplantation. Within the same year, Austrian surgeon Emerich Ullmann
performed the first experimental kidney transplantation in animals in Vienna. Dr. Joseph E. Murray
performed the first successful living-related kidney transplantation between identical twins in 1954
and was awarded the Nobel Prize for this pioneering effort in 1990. Giuseppe Baronio’s (1758–1814)
contributions are considered fundamental to the field of plastic surgery, and he laid the groundwork
for research in the fields of both skin grafting and transplant immunology. Gaspare Tagliacozzi was
a surgeon in the 16th century who emerged as a popular figure in transplantation and was a
specialist in rhinoplasty. Thomas E. Starzl performed the first human liver transplant in 1967 at the
University of Colorado in Denver and has often been referred to as the father of modern transplantation.
mebooksfree.net

References
Guild, WR, Harrison, JH, Merrill, JP, Murray, J. Successful homotransplantation of the kidney in an identical twin. Trans Am Clin Climatol
Assoc. 1956;67:167-173.
Rana, A, Gruessner, A, Agopian, VG, et al. Survival benefit of solid-organ transplant in the United States. JAMA Surg. 2015;50(3):252-259.
Shores, JT, Brandacher, G, Lee, WP. Hand and upper extremity transplantation: an update of outcomes in the worldwide experience. Plast
Reconstr Surg. 2015;35(2):351e-360e.This review provides a comprehensive overview of the current status and outcomes after upper extremity
transplantation globally.
Brandacher, G. Composite tissue transplantation. Methods Mol Biol. 2013;1034:103-115.
Petruzzo, P, Lanzetta, M, Dubernard, JM, et al. The International Registry on hand and composite tissue transplantation. Transplantation.
2010;90(12):1590-1594.
Fryer, M, Grahammer, J, Khalifian, S, et al. Exploring cell-based tolerance strategies for hand and face transplantation. Expert Rev Clin
Immunol. 2015;11(11):1189-1204.
Brandacher, G, Lee, WP, Schneeberger, S. Minimizing immunosuppression in hand transplantation. Expert Rev Clin Immunol. 2012;(7):673-
683.
Brandacher, G, Khalifian, S, Lee, WPA. Reconstructive transplantation: from scientific dream to clinical reality. The Science of Reconstructive
Transplantation. New York, NY: Humana Press; 2015.
Bhishagratna, KL. Sushruta Samhita. Vol 1. 1907. Forgotten Books.
Martin, C. John Hunter and tissue transplantation. Surg Gynecol Obstet. 1970;131(2):306.
Schultheiss, D, Bloom, DA, Wefer, J, Jonas, U. Tissue engineering from Adam to the zygote: historical reflections. World J Urol. 2000;18(1):84-
90.
Billingham, RE, Brent, L, Medawar, PB. Actively acquired tolerance of foreign cells. Nature. 1953;172(4379):603-606.
Merrill, JP, Murray, JE, Takacs, FJ, et al. Successful transplantation of kidney from a human cadaver. JAMA 1963;185:347-353.
Starzl, TE. History of clinical transplantation. World J Surg. 2000;24(7):759-782.
Gilbert, R. Transplant is successful with a cadaver forearm. Med Trib Med News. 1964;5:20.
Jones, JW Jr, Ustuner, ET, Zdichavsky, M, et al. Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate
mofetil therapy. Surgery. 1999;126(2):384-388.
Dubernard, JM, Owen, E, Herzberg, G, et al. Human hand allograft: report on first 6 months. Lancet. 1999;353:1315-1320.
Shores, JT, Malek, V, Lee, WPA, Brandacher, G. Outcomes after hand and upper extremity transplantation. J Mater Sci Mater Med. 2017;(5):72.
Devauchelle, B, Badet, L, Lengele, B, et al. First human face allograft: early report. Lancet. 2006;368(9531):203-209.
Khalifian, S, Brazio, PS, Mohan, R, et al. Facial transplantation: the first 9 years. Lancet. 2014;384(9960):2153-2163.
Tasigiorgos, S, Kollar, B, Krezdorn, N, et al. Face transplantation-current status and future developments. Transpl Int. 2018;(7):677-688.This
review provides a comprehensive overview of the current status and outcomes after upper extremity transplantation globally. This review provides an
excellent summary of the current status and latest developments of the field of face transplantation.
Strome, M, Stein, J, Esclamado, R, et al. Laryngeal transplantation and 40-month follow-up. N Engl J Med. 2001;344:1676-1679.
Delaere, P, Vranckx, J, Verleden, G, et al. Tracheal allotransplantation after withdrawal of immunosuppressive therapy. N Engl J Med.
2010;362(2):138-145.
Hofmann, GO, Kirschner, MH. Clinical experience in allogeneic vascularized bone and joint allografting. Microsurgery. 2000;20(8):375-383.
Levi, DM, Tzakis, AG, Kato, T, et al. Transplantation of the abdominal wall. Lancet. 2003;361(9376):2173-2176.
McDiarmid, SV. Donor and procurement related issues in vascularized composite allograft transplantation. Curr Opin Organ Transpl. 2013;
(6):665-671.
Ali, JM, Bolton, EM, Bradley, JA, Pettigrew, GJ. Allorecognition pathways in transplant rejection and tolerance. Transplantation.
2013;96(8):681-688.
DeWolf, S, Sykes, M. Alloimmune T cells in transplantation. J Clin Invest. 2017;127(7):2473-2481.
Halloran, PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715-2729.
Borges, TJ, Murakami, N, Riella, LV. Current status of alloimmunity. Curr Opin Nephrol Hypertens. 2016;(6):556-562.
Etra, JW, Raimondi, G, Brandacher, G. Mechanisms of rejection in vascular composite allotransplantation. Curr Opin Organ Transpl. 2018;
(1):28-33.
Wiseman, AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016;11(2):332-343.An excellent overview of immunosuppressive agents in
current use in transplantation and their individual mode of action.
Agarwal, A, Ally, W, Brayman, K. The future direction and unmet needs of transplant immunosuppression. Expert Rev Clin Pharmacol. 2016;
(7):873-876.
Schwarz, C, Mahr, B, Muckenhuber, M, Wekerle, T. Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results.
Expert Rev Clin Immunol. 2018;(7):583-592.
Zuber, J, Sykes, M. Mechanisms of mixed chimerism-based transplant tolerance. Trends Immunol. 2017;(11):829-843.A comprehensive discussion
of the principles and underlying mechanisms of mixed chimerism-based tolerance induction in solid organ transplantation.
mebooksfree.net

Mahr, B, Granofszky, N, Muckenhuber, M, Wekerle, T. Transplantation tolerance through hematopoietic chimerism: progress and challenges
for clinical translation. Front Immunol. 2017;8:1762.
Vaikunthanathan, T, Safinia, N, Lombardi, G. Optimizing regulatory T cells for therapeutic application in human organ transplantation. Curr
Opin Organ Transpl. 2018;23(5):516-523. doi: 10.1097/MOT.0000000000000561.
Wendt, JR, Ulich, TR, Ruzics, EP, Hostetler, JR. Long-term survival of human skin allografts in patients with immunosuppression. Ann Plast
Surg. 2004;113(5):411-417.
Mackinnon, SE, Doolabh, VB, Novak, CB, Trulock, EP. Clinical outcome following nerve allograft transplantation. Plast Reconstr Surg.
2001;107(6):1419-1429.
Howsare, M, Jones, CM, Ramirez, AM. Immunosuppression maintenance in vascularized composite allotransplantation: what is just right?
Curr Opin Organ Transpl. 2017;(5):463-469.
Schneeberger, S, Khalifian, S, Brandacher, G. Immunosuppression and monitoring of rejection in hand transplantation. Tech Hand Up Extrem
Surg. 2013;17(4):208-214.
Kueckelhaus, M, Fischer, S, Seyda, M, et al. Vascularized composite allotransplantation: current standards and novel approaches to prevent
acute rejection and chronic allograft deterioration. Transpl Int. 2016;(6):655-662.
Cetrulo, CL Jr, Drijkoningen, T, Sachs, DH. Tolerance induction via mixed chimerism in vascularized composite allotransplantation: is it time
for clinical application? Curr Opin Organ Transplant. 2015;(6):602-607.
Vyas, KS, Mohan, AT, Morrison, SD, et al. Cell-based therapies in vascularized composite allotransplantation. J Reconstr Microsurg.
2018;34(8):642-650. doi:10.1055/s-0038-1661336.
Giatsidis, G, Sinha, I, Pomahac, B. Reflections on a decade of face transplantation. Ann Surg. 2017;5(4):841-846.
Brännström, M, Johannesson, L, Bokström, H, et al. Livebirth after uterus transplantation. Lancet. 2015;385(9968):607-616.Seminal report of the
pioneering efforts and the first livebirth after uterus transplantation.
Brännström, M. Womb transplants with live births: an update and the future. Expert Opin Biol Ther. 2017;17:1105-1112.
Huet, S, Tardieu, A, Filloux, M, et al. Uterus transplantation in France: for which patients? Eur J Obstet Gynecol Reprod Biol. 2016;205:7-10.
Tuffaha, SH, Cooney, DS, Sopko, NA, et al. Penile transplantation: an emerging option for genitourinary reconstruction. Transpl Int. 2017;
(5):441-450.
van der Merwe, A, Graewe, F, Zühlke, A, et al. Penile allotransplantation for penis amputation following ritual circumcision: a case report
with 24 months of follow-up. Lancet. 2017;390(10099):1038-1047.Seminal report of the first successful penis allotransplanation.
Cetrulo, CL Jr, Li, K, Salinas, HM, et al. Penis transplantation: first US experience. Ann Surg. 2018;7(5):983-988.
mebooksfree.net

C H A P T E R 9
mebooksfree.net

Principles of Prosthetics in Plastic Surgery
Ara A. Salibian and Ernest S. Chiu
Key Points
Prosthetics, when used appropriately, can successfully provide a variety of restorative functions
including permanent reconstruction of osseous and soft tissue defects, reinforcement of complex
wound closures, stabilization of bony discontinuities, optimization of autologous tissue for
reconstruction, and augmentation of aesthetic features.
The ideal prosthetic should minimize foreign body reactions, incorporate into the surrounding
tissues, resist infection, retain its shape, easily be implanted and manipulated, and be permanent.
Implantation of prosthetics requires strict sterile technique, minimization of handling by multiple
personnel, use of antibiotic solutions, and limitation of contact with skin or other potential sources of
infection.
Facial prosthetics can provide excellent cosmetic results, alone or in combination with autologous
techniques for skeletal augmentation as well as bony and soft tissue reconstruction with the
appropriate implant choice, incision design with respect for aesthetic subunits, and proper implant
placement in the subperiosteal plane.
Success with temporary implants for tissue expansion relies on good soft tissue coverage,
appropriate implant shape and position, controlled expansion, patient counseling, and patience.
The use of prosthetics for skeletal and soft tissue augmentation requires balancing the requests of the
patient with the surgeon’s understanding of what is medically appropriate for each individual
patient.
The most common complications with prosthetics are infection and extrusion, which can be
minimized by adherence to the aforementioned principles but must be addressed promptly if present
for eventual reconstructive salvage.
A thorough preoperative discussion of the potential risks of prosthetics is crucial, including the need
for explantation as well as other rare and serious complications such as implant-associated neoplasm.
mebooksfree.net

Background
Prosthetics are a subset of biomaterials or substances used to support, augment, or replace a particular
tissue or group of tissues of function in the body. 1 Prosthetics have a variety of critical functions as an
adjunct to or a replacement of autologous methods of reconstruction and augmentation. Lack of
availability of adequate autologous material for reconstruction may require the use of synthetic
compounds. At other times, an implant can enhance the reconstructive capabilities of autologous tissue,
as with mechanical and biologic creep, 2,3 or can support the healing of autologous structures, as with
titanium internal fixation of fractures. Implants can also be used in aesthetic surgery to augment the
appearance of the facial skeleton, or enhance volume and soft tissue contours throughout the body.
The utilization of prosthetic implants requires adherence to basic guidelines, many of which parallel
general plastic surgery principles. All implants should be meticulously handled using strict sterile
technique and limited contact with personnel, skin and external surfaces. Implantation requires creation
of an adequate pocket in the appropriate tissue planes that provides a well-vascularized environment to
prevent infection and extrusion and minimize palpability and visibility. Along the same lines, infected,
irradiated, and poorly vascularized tissue must be avoided.
The ideal prosthetic implant has long been sought after and unfortunately has still not been developed.
There is a commonality of important characteristics to minimize complications from prosthetics and
maximize their benefits. These central traits were outlined by Cumberland 4 and Scales 5 in the 1950s.
They can be summarized as principles pertaining to the utility of an implant such as its ability to be
adaptable but still resist mechanical strain as well as requirements for safety and compatibility such as
minimizing inflammation and cellular foreign body responses (Table 9.1). Considering these
characteristics when determining the need for a prosthetic can help guide the appropriate utilization of
implants.
TABLE 9.1
Characteristics of Ideal Prosthetic Implants 4,5
Allow for tissue ingrowth
Nonallergenic
Noncarcinogenic
Sterilizable
Permanence (when indicated)
Minimize foreign body reaction
High tolerance for mechanical stress
Easily fabricated at low cost
Adaptable
Easy to manipulate and handle
Resistant to infection
mebooksfree.net

mebooksfree.net

History
The search for adequate replacements of damaged or missing bodily structures is not a recent
phenomenon. Implantable materials have been traced back to the use of suture over 32,000 years ago and
later to the ancient Egyptians. 6 Dental fillings made of beeswax have been found in Neolithic mandibles
that are 6500 years old. 7 Trephination defects from Peru dating to 3000 BC have been found to be filled
with various materials from gold and silver to shells. 8
Limitations of early prosthetic implantation were several, and included the nature of materials utilized as
well as the handling of these items that would inevitably lead to breakdown, infection and failure. The
concept of aseptic technique, introduced in the 19th century, 9 was a critical scientific advancement for the
successful utilization of implants. The development of radiography in the late 19th century 10 was also a
major milestone, as many of the initial modern implants consisted of metal internal fixation hardware for
fractures since introduced in 1895. 11
The 20th century marked the transition from the reliance on natural materials for implants to the
development of metal alloys, ceramics, and polymers. The infamous accidental discovery of the
suitability of a plastic polymer as a prosthetic after the traumatic implantation of the material led Harold
Ridley to utilize PMMA for artificial lenses in 1949. 6 Soon thereafter Arthur Voorhees used fabric grafts
to develop arterial prostheses, 12 and Cumberland described nylon mesh for ventral hernia. 4 Major strides
continued in the mid-20th century as scientists worked to improve the applicability and biocompatibility
of implants, an effort that persists today.
mebooksfree.net

The Foreign Body Response
The foreign body reaction is the body’s immunologic response to implantation of a nonhost material. The
reaction is mediated by a cascade of molecular factors initiated by platelets, fibrinogen, and complement
proteins that results in a chronic inflammatory state with the recruitment of macrophages, the formation
of foreign body giant cells, and the persistence of inflammation and eventually fibrosis. 13 The extent of
this response is influenced by the nature of the implant.
Biocompatibility of an implanted prosthetic characterizes the ability of the device to coexist within the
host. This concept has migrated away from describing an inert material in isolation from the body to
representing a mutual but favorable interaction between the implant and the host. With regard to
implantable devices, biocompatibility can be redefined as the ability of the device to perform its intended
function, with the desired degree of incorporation in the host, without eliciting any undesirable local or systemic
effects in that host. 1
The long-term implications of the foreign body response can be practically divided into two end points:
fibrous encapsulation versus tissue incorporation. Fibrous encapsulation of an implant results in a dense
scar plate around the foreign, whereas tissue incorporation results in more random extracellular matrix
deposition, cellular infiltration, and neovascularization. 14 The characteristics of a particular implant, such
as pore size, can significantly impact which pathway predominates. 15 Macroporous mesh will allow
tissue to cross pores and promote mesh incorporation whereas microporous mesh prevents cell migration
and results in mesh encapsulation.
mebooksfree.net

Implant Materials
Different prosthetic materials have different reconstructive implications with regard to physical
properties, interaction with the surrounding tissues, management of complications, and long-term
retention. Although many different implant materials have been used historically, this review will
summarize only the most commonly used synthetic materials (Table 9.2).
TABLE 9.2
Common Prosthetic Implant Materials
Metals
Stainless steel
Titanium
Gold
Platinum
Ceramics
Hydroxyapatite
Tricalcium phosphate
Calcium phosphate cement
Polymers
Polyester
Polyethylene
PMMA
Polypropylene
Expanded polytetrafluoroethylene
Polyurethane urea
Silicone
Biodegradable polymers
mebooksfree.net

Metals
Initial metal implants, typically for fracture fixation, suffered from corrosion. 11 It was not until the
refinement of different combination of metals, or alloys that promoted the more widespread applicability
of metal implants. Key characteristics of biocompatible metal implants include nontoxicity, resistance to
corrosion, ability to osseointegrate (when needed), appropriate mechanical properties and high wear
resistance, or resistance to loss of surface material secondary to mechanical forces. 16
mebooksfree.net

Stainless Steel
Stainless steel refers to a number of iron-based alloys that usually contain a high percentage of chromium
and varying amounts of nickel. Stainless steel has a high tensile strength and elastic modulus as well as
low cost and was one of the earlier alloys to be utilized for medical implants. Stainless steel, however, is
limited by its poor resistance to fatigue as well as corrosion, which has resulted in premature failure of
these implants. Stainless steel also has poor wear resistance that results in debris that can induce
inflammation and allergic reactions. In addition, leaching of nickel and chromium from the alloy has been
shown to be toxic. These characteristics limit the utility of this alloy in long-term applications. Currently,
stainless steel is most often used for temporary implants such as surgical wires and arch bars for
maxillomandibular fixation.
mebooksfree.net

Titanium
Titanium is utilized as a pure low-density chemical element or a stronger but less malleable alloy usually
combined with aluminum and vanadium. This alloy was developed more recently and has replaced
many of its prior counterparts such as stainless steel and vitallium. The most important properties of
titanium include its low density, high strength-to-density ratio, inert character, and high resistance to
corrosion secondary to formation of a protective stable oxide layer. 17 It is therefore considered to be the
most biocompatible of metals, which has led to its widespread use in implantable medical devices.
Titanium also has a lower modulus of elasticity than stainless steel and cobalt-chromium alloys. 16 This
modulus more closely matches that of bone and therefore decreases stress shielding, allowing for more
loading of bone. Titanium integrates with bone without formation of an intervening fibrous capsule,
which allows it to be used for osseointegrated implants. Furthermore, titanium is nonferromagnetic and
therefore does not preclude patients from undergoing magnetic resonance imaging. In the realm of
plastic surgery, titanium is primarily utilized for osteosynthesis plates and screws (Figure 9.1),
maxillofacial implants, and cranioplasty.
FIGURE 9.1 Titanium mandible plate and mini-plate with screws to provide rigid fixation of a comminuted parasymphyseal
fracture. Also pictured are stainless steel arch bars and wire for placement in temporary maxillomandibular fixation.
mebooksfree.net

Gold
Gold has been used for medicinal purpose since ancient civilization. It is a useful metal implant owing to
its resistance to corrosion and nontoxic and highly inert character. Pure gold does not react with any
known substances in the body. Although gold is very malleable, it lacks strength, limiting its
applications. The most common use of gold implants is for upper eyelid weight in the treatment of
lagophthalmos secondary to facial nerve palsy. These implants typically are purer 24-carat gold alloys to
maximize nonreactivity and biocompatibility.
mebooksfree.net

Platinum
Platinum is a dense and malleable chemical element. Plastic Surgery applications are primarily for eyelid
weights for treatment of paralytic lagophthalmos. The higher density of platinum than gold allows for the
use of smaller, lower profile implants. The high malleability of platinum is also beneficial when molding
of an implant is needed. Platinum is also used in the cross-linking of medical-grade silicone or
poly(dimethylsiloxane) (PDMS) in silicone breast implants.
mebooksfree.net

Calcium Ceramics
Ceramics are inorganic compounds with a spectrum of crystalline structures. The most commonly used
ceramic implants in plastic surgery are calcium phosphate–based ceramics typically utilized as alloplastic
bone substitutes. These materials are typically porous, allowing for tissue ingrowth and osteoconductive.
A critical limitation of the widespread application of calcium phosphates is their mechanical properties.
These cements have low impact resistance and low tensile strength and are brittle, limiting their use in
any load-bearing areas. They are therefore typically used for reconstruction, and less so, augmentation of
the craniofacial skeleton. The most common ceramics are hydroxyapatite, Ca10(PO4)6(OH)2; tricalcium
phosphate, Ca3(PO4)2; and derivatives of calcium phosphate cement pastes.
mebooksfree.net

Hydroxyapatite
Hydroxyapatite is formed from naturally occurring calcium carbonate coral and has organized porous
channels. It is available in particulate and block forms that can be carved to fit a cranioplasty defect, as
well as bone cement pastes that set isothermally and have decreased radiologic scatter. These cement
pastes (Mimix [Walter Lorenz Surgical, Inc., Jacksonville, FL]; BoneSource [Stryker Leibinger, Portage,
MI]) have been widely use in craniofacial reconstruction, usually for cranioplasty 18,19 but also for
interpositional bone grafts in orthognathic surgery. Hydroxyapatite is osteoconductive, but as a
microporous cement, direct bony and vascular ingrowth is limited, and bony replacement tends to occur
by resorption and turnover of hydroxyapatite to bone at the periphery of the implant.
mebooksfree.net

Tricalcium Phosphate
Tricalcium phosphate is a synthetic, porous ceramic that, like hydroxyapatite, provides a scaffold for
tissue ingrowth. It has more random pore structure and is more quickly resorbed and replaced by bone
than hydroxyapatite. It is also available both in block and particulate form.
mebooksfree.net

Carbonated Calcium Phosphate Cement
Carbonated calcium phosphate pastes have also been developed from calcium phosphate and calcium
carbonate. Dahllite, a carbonated apatite (Norian Cranial Repair System, Synthes, Paoli, PA), has higher
tensile and compressive strength and a composition that closely resembles bone. 20 This carbonated
apatite cement has been shown to have a greater resistance to fracture when compared with
hydroxyapatite cement products. 21 The solubility of dahllite at a lower pH has been suggested to increase
resorption and replacement by natural bone.
mebooksfree.net