Phẫu Thuật Tạo Hình (Tập 1): Nguyên Lý Cơ Bản – Neligan (2018)

617
Conclusion
osseointegrated prosthetic reconstruction adds another floor
where the reconstructive elevator can stop.
The future of craniofacial osseointegration includes the
development of new implants and implant surfaces to stimu-
late bone formation and remodeling to improve long-term
success. Growth factors, stem cells, and new drugs will help
improve success rates in compromised tissues. Further
developments using advanced digital technologies such as
rapid prototyping,65,66 image acquisition technology,67 software
manipulation systems, and color-matching software,68 will
make prosthetic reconstruction more accurate, faster, and
potentially cheaper. New methods of noninvasive testing will
allow better evaluation of implants, and better strategies to
prevent implant loss will be devised.69 Presently skin does not
attach to the percutaneous abutment so the connection is
maintained essentially as an open wound. Improved under-
standing of this soft-tissue interface will allow for more use
elsewhere in the body, including the extremities, where con-
tamination is more common.70 Combining osseointegration
technology with microelectronics could produce movable or
sensory prosthetics71–74 or some type of seeing orbital prosthe-
sis.75 Large titanium implants will secure large-extremity
prosthetics better.76,77 The future is exciting for a whole field
of endeavor that started with the chance observation by P.I.
Brånemark of an unusual behavior of a metal in a blood flow
study in rabbits!
system, 55% felt that they had a skin reaction; however, 83%
did not consider their reaction severe. Ultimately most patients
were satisfied (97% satisfied, and 74% very satisfied). In all,
94% would ultimately undergo the same procedure again and
97% would recommend it to others.
Conclusion
Craniofacial osseointegration has an important role in the
treatment of major head and neck defects. It offers treatment
options in many situations where in the past only poor ones
existed. Patient satisfaction is very high and they often become
strong advocates for this treatment modality. Craniofacial
Fig. 31.18  Adverse skin reactions can intermittently be a problem requiring
treatment. Lower abutment shows no soft-tissue reaction while upper abutment
shows some tissue hypertrophy.
Bonus images for this chapter can be found online at

Fig. 31.1 Historical development of osseointegration biotechnology. Through
the Brånemark experience, osseointegrated implants have been subjected to
over 30 years of scientific scrutiny. Craniofacial applications were first
introduced in 1977. EO, extraoral.
9. Parel SM, Brånemark PI, Tjellström A, et al. Osseointegration in
maxillofacial prosthetics. Part II: extraoral applications. J Prosthet
Dent. 1986;55:600–606. The role of osseointegrated fixtures in facial
reconstruction is discussed. Advantages over adhesive systems are
highlighted.
13. Brånemark PI, Hansson BO, Adell R, et al. Osseointegrated
implants in the treatment of totally edentulous jaws: experience
from a 10-year period. Scand J Plast Reconstr Surg Suppl. 1977;1:16.
16. Albrektsson T, Brånemark P, Jacobsson MD, et al. Present clinical
applications of osseointegrated percutaneous implants. Plast
Reconstr Surg. 1987;79:721–730. This is a large case series cataloging
outcomes in 174 patients treated with osseointegrated percutaneous
implants for external hearing aids or facial epistheses.
17. Tjellström A. Osseointegrated implants for replacement of absent or
defect ears. Clin Plast Surg. 1990;17:355–366.
20. Wilkes GH, Wolfaardt JF. Osseointegrated alloplastic versus
autogenous ear reconstruction: criteria for treatment selection. Plast
Reconstr Surg. 1994;93:967–979. The authors review a series of
autogenous and prosthetic auricular reconstructions. Criteria for each
technique were developed based on the authors’ experience.
26. Brent B. Technical advances in ear reconstruction with autogenous
rib cartilage grafts: personal experience with 1200 cases. Plast
Reconstr Surg. 1999;104:319–334. The author presents his extensive
experience with rib cartilage-based auricular reconstruction. Topics from
cartilage-sparing technique to tissue engineering are discussed.
32. Nagata S. A new method of total reconstruction of the auricle for
microtia. Plast Reconstr Surg. 1993;92:187–201. The author presents a
two-stage method for total-ear reconstruction, dividing the procedure first
into designing and placing the costal cartilage framework and second into
elevating the completed construct.
46. Granström G. Radiotherapy, osseointegration and hyperbaric
oxygen therapy. Periodontol 2000. 2003;33:145–162.
57. Harris L, Wilkes GH, Wolfaardt JF. Autogenous soft tissue
procedures and osseointegrated alloplastic reconstruction: their role
in the treatment of complex craniofacial defects. Plast Reconstr Surg.
1996;98:387–392.
63. Westin T, Tjellström A, Hammerlid E, et al. Long-term study of
quality and safety of osseointegration for the retention of auricular
prostheses. Otolaryngol Head Neck Surg. 1999;121:133–143.
Access the complete reference list online at

617.e1
References
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32 
Transplantation in plastic surgery
David W. Mathes, Peter E.M. Butler, and W.P. Andrew Lee
SYNOPSIS
■ The most important antigens contributing to allograft rejection are the
major histocompatibility complex (MHC) antigens.
■ The immune system has two main arms that mediate both rejection
and tolerance to foreign antigens: the humoral response (B cells and
antibodies) and the cell-mediated response (T cells).
■ T lymphocytes have a central role in coordinating the immune
response, forming the cell-mediated arm of the immune response.
■ Acute rejection takes place days to weeks after transplantation and
occurs with rapid onset. This T-cell-mediated response is characterized
by fever, graft tenderness, and edema, and loss of function. Interstitial
lymphocytic infiltration is seen on microscopic examination.
■ Chronic rejection is characterized by fibrosis and severe organ
dysfunction. This process usually occurs over years.
■ Immunosuppressive medications must inhibit the body’s ability to
reject a transplanted organ, but not at the expense of the defense
network against pathogens.
■ Despite the use of powerful immunosuppressive medications most
transplant patients experience episodes of acute rejection.
■ Two major issues in hand transplantation are the need for maintenance
immunosuppression and the evaluation of the functional outcomes of
the transplants.
■ Clinical hand and face transplantation have expanded over the past 5
years but still are limited by the need for chronic immunosuppression
and the threat of rejection.
The fields of transplantation and plastic surgery have always
been closely linked. In fact, the age of organ allotransplanta-
tion in the US began when Joseph E. Murray, a plastic surgeon,
transplanted a kidney between identical twin brothers in
1955.1 Such “reconstructive surgery” using organ allografts
was one of the great achievements in 20th-century medicine.
Plastic surgeons often reconstruct tissue defects via transplan-
tation of autologous tissue from other regions of the body.
Nonvascularized skin, bone, and cartilage grafts alone or in
combination with axial and random flaps are common every-
day procedures used to reconstruct tissue defects. However,
these surgical techniques all have significant limitations, often
require revisions, and leave the patient with a donor site.
Advances in the development of skin substitutes (prepared
from allogeneic or xenogeneic sources) and the application of
frozen bone allografts have shown the possibility of recon-
struction without a donor site but their application is limited.
Despite advances in plastic and reconstructive surgery,
including the refinement of microvascular techniques and
delineation of flap vascular anatomy, many complex wounds,
especially those on the central face, still remain outside the
realm of possibility for restoring both form and function.
The inability to reconstruct missing tissues accurately
occurs when the surgeon must deviate from the principle of
replacing “like with like” due to a lack of appropriate autolo-
gous donor sources. Thus, the function of a severely injured
extremity cannot be adequately restored, the appearance of a
severely disfigured face cannot be satisfactorily improved,
and both the function and appearance of an amputated
extremity cannot be reconstructed. Understandably, the incli-
nation toward tissue transplantation has led plastic surgery
researchers to look to non-autogenous sources for reconstruc-
tive material.2–4 However, the ability to engineer tissue from
single cell sources has yet to yield a technique that can provide
the complex tissue constructs needed. One technique with the
potential for providing access to complex vascularized tissue
constructs without the need for a donor site is through the
process of allotransplantation.
The clinical feasibility of vascularized composite allograft
(VCA) has been demonstrated by the successful transplanta-
tion of over 107 hands and 37 faces worldwide.5–11 The field
of reconstructive transplantation represents a paradigm shift
in the arena of reconstructive surgery. The application of these
transplants to patients with complex wounds can provide the
reconstructive surgeon with the opportunity to reconstruct
with the exact tissues lost. However, unlike traditional solid-
organ transplants (kidney, liver, and heart) that consist of
relatively homogenous parenchymal tissue, the vascularized
composite allograft is comprised of multiple heterogeneous
tissue types (skin, bone, and muscle). Each of these distinct

619
Transplantation immunology
Class I antigens are expressed on nearly all nucleated cells and
serve as the primary target for cytotoxic (CD8+) T lympho-
cytes. Class II MHC genes encode two noncovalently bound
transmembrane proteins, a 34-kDa α chain and a 29-kDa β
chain. There are three class II loci in humans: HLA-DR,
HLA-DP, and HLA-DQ.15 Class II antigens are expressed
primarily on vascular endothelium and cells of hematopoietic
stem cell origin such as lymphocytes and macrophages.
Both class I and class II molecules have a specific site at
which foreign peptide antigens can be presented after they
have been processed by the cell.16–19 Tissue distribution is not
the same in all species: humans, dogs, pigs, and monkeys
express class II antigens on endothelial cells, whereas rodents
and many species do not.20 Matching of HLA-A, HLA-B, and
HLA-DR has been found to be an important factor in deter-
mining long-term renal allograft survival.21
Other transplant antigens
In addition to the MHC antigens, there are three other classes
of surface proteins: ABO blood group proteins, minor histo-
compatibility antigens, and skin-specific antigens.
The blood group antigens are important in clinical trans-
plantation because they are expressed on vascular endothelial
cells. Patients with type A or type B blood develop natural
antibodies to the other protein, whereas patients with type O
blood develop natural antibodies to both type A and type B
proteins. Although ABO antigens will not stimulate cell-
mediated rejection, a brisk antibody-mediated attack can
rapidly lead to graft failure.22
Minor histocompatibility antigens are peptides of self
origin that are not presented by the MHC complexes. Siblings
(other than identical twins) with a completely matched MHC
profile will still differ with respect to minor antigens because
of allelic variation of the genes encoding those proteins.
Although minor antigens will stimulate a cell-mediated
response, they will not do so in a primary in vitro test. Rejec-
tion of a graft due to minor antigens alone, therefore, often
proceeds at a slower rate.23
Skin-specific antigens (Sk antigen) are tissue-specific pro-
teins that can cause graft rejection by a cell-mediated response.
Consequently, skin is one of the most difficult tissues to which
transplantation tolerance can be induced.24
Immunologic rejection cascade
Cells of immune response
A number of cells with varied but interconnected functions
participate in the process of graft rejection. They work together
to maintain the two main arms of the immune reaction, the
humoral response (B cells and antibodies) and the cell-
mediated response (T cells).
Macrophages
The macrophage performs the most ancient cellular defense
function: phagocytosis. It is of mesenchymal origin and
thought to arise from a bone marrow stem cell. It can freely
circulate throughout the body, migrate through lymph nodes,
or remain stationary within tissues. Kupffer cells are special-
ized macrophages that reside in the liver. The Langerhans cell
is a specialized macrophage that is specific to the skin. The
tissue types has been shown to exhibit varying degrees of
antigenicity, with skin and mucosa the most antigenic.12 While
solid-organ transplantation is the gold standard for the treat-
ment of end-stage organ failure, there has yet to be true con-
sensus on the use and application of vascularized composite
allografts.13,14 The survival of the hand and face transplants is
dependent on the use of chronic immunosuppression and
their application is currently limited to experimental institu-
tionally approved protocols. In order for the field of recon-
structive transplantation to expand its indications beyond the
experimental arena, techniques need to be designed either to
significantly reduce or eliminate the need for chronic immu-
nosuppression. The future direction of this field is heavily
dependent on the development of innovative approaches to
the use of immunosuppressive agents and tolerance induction
protocols.
Nomenclature
A graft is nonvascularized tissue (such as skin) that is har-
vested from its donor bed and transferred to a recipient site.
Its survival relies on ingrowth of new vessels from the recipi-
ent bed to restore its blood supply. In contrast, a flap involves
the transfer of vascularized tissue (such as muscle and skin)
via either the preservation of an axial blood vessel or micro-
vascular anastomoses of that vessel to recipient vessels located
adjacent to the wound. An autograft is tissue transplanted
from one location to another in the same individual. An iso-
graft is transplanted from a genetically identical donor to the
recipient, such as transplants between syngeneic mice and
human monozygotic twins. An allograft is transplantation of
tissues between unrelated individuals of the same species. A
xenograft is transplantation between different species.
Transplantation may also be described in terms of the site
into which the tissue is transplanted. Orthotopic refers to
transplantation into an anatomically similar site; heterotopic
refers to transplantation into an anatomic site different from
the site of origin.
Transplantation immunology
Major histocompatibility complex
The most important antigens contributing to allograft rejec-
tion are the major histocompatibility complex (MHC) antigens.
The MHC proteins are encoded in a gene complex on the
short arm of chromosome 6 and have different nomenclature
between species: human leukocyte antigen (HLA) in humans,
swine leukocyte antigen (SLA) in swine, H-2 in mice, and RT1
in rat. MHC genes are expressed in a codominant fashion,
with one haplotype, or set of alleles, inherited from each
parent.
There are two major classes of MHC genes. Class I MHC
genes encode a transmembrane glycoprotein complex with a
polymorphic 44-kDa heavy chain consisting of three extracel-
lular domains (α1, α2, and α3). The α1 domain is highly variable
and contains sites for antigen binding. The heavy chain is
stabilized by noncovalent binding to a lighter chain, referred
to as β2-microglobulin. There are three distinct genetic loci for
the class I antigens in the human: HLA-A, HLA-B, and HLA-C.

620
CHAPTER 32 • Transplantation in plastic surgery
Finally, they display immunoglobulin on their surface. When
stimulated, the B lymphocyte differentiates into plasma cells.
These smaller cells serve as factories to produce specific
antibodies. These soluble antibodies support the humoral arm
of the immune response. Through rearrangement of a highly
variable genetic region during immune development, anti-
bodies are produced that can bind countless millions of dif-
ferent epitopes.
Immunoglobulin
Antibodies produced by B lymphocytes and plasma cells take
the form of immunoglobulins. Immunoglobulins are proteins
of unique structure, composed of heavy and light peptide
chains. The “root” of the heavy-chain complex is called the
constant fragment. The portion of an immunoglobulin mole-
cule where light chains form complexes with heavy chains, at
the site at which the antibody will bind to its target, is desig-
nated the antibody-binding fragment (Fab). Myriad possibili-
ties exist for antigen to a specific antibody to be made because
the Fab moiety is highly variable in its discrete structure. More
than 100 genes code for specific segments of the variable por-
tions of the heavy and light chains, leading to millions of
potential immunoglobulin specificities.
There are five general immunoglobulin classes: IgM, IgG,
IgE, IgA, and IgD. IgM is the first antibody formed after
exposure to common microbial antigens, followed by the
more durable IgG. IgE is involved in the hypersensitivity
reaction by binding to and activating specialized eosinophils
(mast cells). IgA is secreted in saliva, tears, and breast milk
and thus augments resistance to infection in these fluids. IgD
is found on the surface of immature B lymphocytes; its func-
tion remains unclear. Immunoglobulins may be soluble or
bound to a cell’s surface.
The main function of immunoglobulins is to provide opso-
nization and to activate complement. Opsonization occurs
when the Fab fragment of an immunoglobulin binds to its
associated antigen, such as an invading organism. Subsequent
macrophage and monocyte phagocytosis of the antibody-
coated microorganism is then markedly enhanced. Comple-
ment fixation occurs when the antibody–antigen complex
triggers the complement cascade.
Complement
An antigen–antibody complex may initiate the complement
cascade through a classical pathway. Substances such as
endotoxin may, without immunoglobulins, initiate the cascade
through the alternative pathway. Both pathways converge
with the activation of C3. The sequential activation of prote-
ases, which define the complement cascade, results in a tight
cluster of proteins known as the membrane attack complex.
This complex is able to rupture the membranes of foreign
cells. In the normal host, this cascade is kept in check by the
regulatory protein C1 inhibitor.
Dendritic cells
These cells are derived from bone marrow stem cell progeni-
tors and are highly specialized antigen-presenting cells. They
appear to have little to no effector function. They reside in the
intracellular and interstitial space but migrate through the
lymphatics and to the spleen when activated. There they
present their antigens to T-cell-rich areas.
macrophage expresses class I antigens on its cell surface, and
as a highly specialized immune cell, the macrophage also
expresses class II MHC molecules.
Beyond simple destruction of cells, the main purpose of the
macrophage is to reprocess the breakdown products of
ingested cells. These fragments of foreign protein may then
be bundled with a new class II antigen molecule, and during
the bundling process, fragments of the foreign protein come
to reside in the peptide-binding groove of the class II molecule.
When the fragment is exteriorized, it faces outward and is
easily recognized by the immune system as foreign. This
process is known as antigen presentation. Macrophages also
secrete important cytokines,25,26 such as interleukin-1 (IL-1).
This polypeptide can, in a hormonal fashion, stimulate the
immunologic function of responding cells. These cells are
critical to the presentation of foreign antigen.
Natural killer cells
Another primitive cell derived from the bone marrow stem cell
is the lymphocyte (non-T, non-B) called the natural killer (NK)
cell. NK cells are thought to be active in the antitumor
response.27 They are able to demonstrate spontaneous tumori-
cidal properties on exposure to tumor cells. This cell does
not require recognition of MHC molecules or antigen process-
ing (as do T cells and B cells).28 However, the exact method this
cell uses to recognize foreign cells remains unclear. They are
able to kill cells by incorporating a lipophilic protein into the
target cell membrane, which leads to increased permeability
and cell lysis. NK cells also secrete several cytokines, including
interferon-γ, interferon-α, and B-cell growth factor. They may
also serve to eliminate cells that fail to express normal self-
MHC proteins and thereby be self-reactive. Finally, they appear
to serve as a barrier to the engraftment of donor bone marrow
after non-MHC-matched bone marrow transplantation.29
Granulocyte
The granulocyte plays an important role in immune homeo-
stasis. Named for their histologic staining properties, the
three main cell lines are polymorphonuclear cells, eosino-
phils, and basophils. All of the cell lines are derived from the
same bone marrow precursor. As nucleated cells, they all
express class I MHC molecules; however, they do not express
class II MHC antigens. In addition, these cells express a
number of molecules important for their function (including
adhesion and interaction with other immune cells) on their
cell surface. These white blood cells carry granules of toxic
substances (peroxidases) and substances that attract other
white blood cells and cellular elements of the coagulation
cascade. When stimulated, the granulocyte secretes these
granules, initiating local inflammation in a relatively indis-
criminate fashion.
B lymphocyte
Named for their site of origin in the chicken, the bursa of
Fabricius, these cells play a central role in immune defense.
In humans, the bursa equivalent is thought to be the fetal liver
or bone marrow. Once these cells are produced, they migrate
to the lymph node and spleen and appear to remain in these
organs. These cells express class I and II MHC antigens. They
also display a variety of B-cell-specific markers, known as
B1–B8 (through which the lines of B cells can be identified).

621
Transplantation immunology
receptors. Secreted IL-2 also has paracrine function that affects
other T cells in the region, such as CD8 cells, which require
IL-2 for activation but do not produce it themselves. As CD4
cells become further activated, they secrete IL-4 and IL-5,
which stimulate the maturation and proliferation of B lym-
phocytes. Furthermore, there is evidence that two subsets of
CD4 cells, TH1 and TH2, function to enhance alloreactivity and
stimulate antibody production by B cells, respectively. With
such a central role by CD4 cells in cell signaling, it is easy to
understand the severely compromised immune response
from the loss of host CD4 cell function secondary to human
immunodeficiency virus infection.33–36
Antigen recognition and graft rejection
In the case of allograft tissue, foreign antigens would be rec-
ognized by host T cells after being processed by host antigen-
presenting cells and presented in the context of self MHC.
This is termed indirect presentation. In addition, host T cells
can directly recognize donor MHC on donor antigen-
presenting cells, termed direct presentation. This mechanism
helps explain the more vigorous response to allograft tissue
than to foreign peptides alone.37
Clinically, rejection of allograft tissue can proceed at differ-
ent levels of intensity for different tissues. The common
component for rejection of any graft is inflammation. This
may be manifested as a loss of graft function with local or
systemic signs of inflammation. Several distinct clinical syn-
dromes of graft rejection with different time courses have
been noted. These syndromes differ with regard to the under-
lying primary immunologic process.
Hyperacute rejection occurs almost immediately after
perfusion of the allograft with host blood. It is the result of
preformed antibodies to either ABO blood group proteins or
donor MHC molecules enacting a rapid attack on the donor
tissue. Complement activation results in destruction of vascu-
lar endothelial cells and induces rapid thrombosis of vessels
as well as an amplification of the inflammatory signal. Stan-
dard screening before transplantation should detect preformed
antibodies, making hyperacute rejection a rare clinical entity.
Many mammals possess preformed antibodies to other species
that stand as a major obstacle to xenotransplantation.38
Acute rejection takes place days to weeks after transplanta-
tion and occurs with rapid onset. This T-cell-mediated
response is characterized by fever, graft tenderness, and
edema, and loss of function. Interstitial lymphocytic infiltra-
tion is seen on microscopic examination. In addition, severe
forms of acute rejection may include a humoral attack on the
graft, resulting in a vasculitis.39
Chronic rejection is an indolent process occurring months
to years after transplantation. It is characterized by a progres-
sive loss of tissue architecture with fibrosis and mononuclear
cell infiltration. The etiology of chronic rejection is not well
understood and may be multifactorial. The process may be
slowed because of immunosuppression. It also may result
from the cumulative effect of damage to the graft from ische-
mia during transplantation, graft infection, or drug toxicity.
Inflammatory mediators in transplantation
In addition to the direct cellular interaction observed during
an immune response there are also multiple inflammatory
mediators involved in immune activation and regulation.
T lymphocytes
T lymphocytes have a central role in coordinating the immune
response, forming the cell-mediated arm of the immune
response. The T lymphocyte is named for its site of origin, the
thymus, and is one of the central elements of the immune
system. T cells derive from fetal stem cells in the thymus and
undergo an extensive process of education and deletion before
being released into the body. The maturing T cells are selected
to recognize self MHC antigens and become tolerant to them.
Those cells that demonstrate too high an affinity to self are
eliminated by clonal deletion. Failure of this process appears
to lead to autoimmunity.
These cells express both class I and class II antigens. In
addition to HLA surface markers, lymphocytes also possess
cell surface markers that serve to distinguish one subpopula-
tion from another within the same individual. These are all
glycoproteins and are described by the common determinant
(CD) nomenclature (e.g., CD3).
Three broad classes of T cells are helper T (TH) cells, cyto-
toxic T cells, and suppressor T cells. All T cells express CD3
on the cell surface. Cytotoxic T cells (cells that effect target cell
killing) express CD8. Suppressor T cells that can buffer and
down-regulate the immune response also express CD8.30,31 TH
cell, however, expresses CD4 and serves to amplify the
immune response through its interaction with other cells and
secretion of critical cytokines. Each T cell expresses a T-cell
receptor (TCR) capable of binding antigen. The TCR, a 90-kDa
heterodimer composed of an α chain encoded on chromo-
some 14 and a β chain encoded on chromosome 7, is located
close to the CD3 antigen and the CD28 antigen. The TCR is
relatively flat and possesses an outward-facing surface. This
“antigen recognition platform” is the critical interface for
foreign peptide in the binding groove. As with B-cell develop-
ment, T cells undergo rearrangement of genes coding for a
hypervariable region on the receptor proteins. This allows a
body’s population of T cells to respond to a nearly limitless
array of foreign antigens, with each individual T cell capable
of binding one specific antigen.
T-cell binding and activation
Although the TCR is capable of binding antigen, it will not
recognize the target molecule by itself.32 The TCR can bind
antigen only if it has been processed and presented by an
antigen-presenting cell together with an MHC molecule; thus,
it recognizes the MHC together with the target antigen. This
limitation of binding is referred to as MHC restriction. CD4
(helper) T cells can only bind antigen presented with MHC
class II molecules; CD8 (cytotoxic) T cells recognize antigen
along with MHC class I proteins. The TH cell is most critical
to the immune response because its activation results in the
production of cytokines that are necessary for the function of
many other immune cells. Binding of a CD4 cell to an antigen-
presenting cell that expresses target antigen together with
MHC class II molecules initiates a predictable cycle of intercel-
lular communication. The antigen-presenting cell is stimulated
to produce the cytokine IL-1, a powerful chemoattractant, a
primary mediator in the acute-phase reaction, and a potent
activator of lymphoid cells. The T cell, in turn, secretes IL-2,
which is a required stimulant for differentiation and prolifera-
tion of T cells. The IL-2 produced by the bound T cell has
autocrine function by binding to newly expressed self IL-2

622
CHAPTER 32 • Transplantation in plastic surgery
is possible to transplant type O donor tissue into type A or
type B recipients, the limited supply of donor organs in the
US makes this practice uncommon.
HLA typing is used to match organs with potential recipi-
ents. Serologic methods are employed to type HLA-A,
HLA-B, and HLA-DR. A heterozygous individual with a
complete match at all these loci is referred to as a six-antigen
match. For renal allografts, HLA matching has been shown
to affect graft survival. Kidneys transplanted from HLA-
identical siblings have a 3-year success rate that well exceeds
90%, whereas parent-to-child grafts have an 82% survival.
Cadaveric kidney grafts have a 70% 3-year survival rate.48
MHC class II matching has been found to be more important
than class I matching for renal transplantation; the reverse
appears to be true for liver transplantation. This would
suggest differences in mechanisms of graft rejection for dif-
ferent tissues.49 Serologic tissue typing has certain limita-
tions. An HLA antigen can be identified only if it is being
searched for with a specific antibody. For example, if only a
single HLA-DR phenotype is identified in donor tissue, the
individual could be either homozygous for that allele or
heterozygous with an unrecognized HLA-DR antigen. This
method of testing fails to type the other class II antigens,
HLA-DP and HLA-DQ.
Crossmatching is a test that detects the presence of pre-
formed donor-specific antibodies in the serum of a particular
recipient. It represents the final definitive screening measure
before transplantation. In this lymphocytotoxicity assay,
donor lymphocytes are incubated with recipient serum and
complement. Cell viability is then assessed by a dye exclusion
technique. A positive crossmatch, indicated by lysis of the
donor lymphocytes, suggests that a hyperacute reaction is
likely to occur. One pitfall of this test, however, is that organ-
specific antibodies may be missed if those antigens are not
expressed on the lymphocytes being evaluated.
Antibody screening is another modality used in clinical
transplantation. Serum from prospective transplant recipi-
ents is routinely tested in a lymphocytotoxicity assay against
a panel of cells from different donors with known HLA
antigens. The percentage of panel cells lysed reflects the
degree of panel-reactive antibody (PRA), demonstrating
HLA antibodies in an individual’s serum. A high PRA
suggests that a patient is unlikely to have a negative cross-
match. This information is used in determining organ
allocation when the tissue must be transplanted quickly.
Individuals are likely to have a high PRA if they have been
sensitized by previous transplantation, pregnancy, or blood
transfusions.
Current immunosuppression for VCA
The multiple pathways and mechanisms employed by the
immune system to defend the body against both extracellular
and intracellular pathogens have presented a significant
barrier to the survival of transplanted allografts. Immunosup-
pressive medications must inhibit the body’s ability to reject
a transplanted organ, but not at the expense of the defense
network against pathogens. The use of several immunosup-
pressive agents has allowed the inhibition of the immune
system that maximizes the protection of the allograft with the
least cost to the body’s overall ability to fight infection and
tumors (Table 32.1).
These include cell adhesion molecules (CAM), cytokines, and
chemokines that are all critical to a functioning immune
system. Cytokines are transient regulatory proteins that a
wide variety of cells can produce in response to stimulation.
These proteins can act locally by binding to a cell from the
same cell line (autocrine) or to the target cell in the vicinity
(paracrine).40 The cytokines are divided into proinflammatory
cytokines (IL-1α, IL-1β, IL-6; tumor necrosis factors: TNF-α,
TNF-β), cytokines involved in T-cell differentiation (IL-2, IL-4,
IL-5, IL-10, IL-12, IL-13, and interferon-γ), and cytokines of
immunoregulatory function belonging to the transforming
growth factor-β family, which primarily promotes wound
healing and fibrosis.40
Chemokines are a subset of cytokines that are currently
defined as small chemotactic cytokines. Chemokines, which
are constitutively expressed, are involved in homeostatic
lymphocyte trafficking to the lymphoid organs and bind to
the cellular component by a specific chemokine receptor. The
main role of proinflammatory chemokines (macrophage
inflammatory protein-1α (MIP-1α), MIP-1β, monocyte che-
moattractant protein-1 (MCP-1), and RANTES) is to attract
neutrophils to an inflammatory site and trigger T lymphocytes
to elicit an additional inflammatory response.41 In humans,
CCR1-positive cells increase in the peripheral blood of renal
allograft recipients before acute rejection.42 In addition, CCR1
mRNA was found to be expressed in cells derived from
biopsies from renal allografts.43 Ruster et al. described an
increased number of CCR1-positive cells in glomeruli during
rejection.44 Mayer et al. reported that the mRNA expression of
CCR1 was associated with the decrease of renal function in
allografts with an acute rejection episode.45 Thus, it is clear
that chemokines play an important role in allograft rejection
and interruption of these interactions could have an impact
on allograft survival.
CAMs play a role in leukocyte migration from the circula-
tion to tissues. Three types of CAM are involved in the
transmigration process: selectins (L-, E-, and P-selectins)
mediating the rolling of leukocytes along the vascular endo-
thelium, integrins (intercellular adhesion molecule-1 (ICAM-
1), vascular CAM-1 (VCAM-1), mucosal addressin cellular
adhesion molecule-1 (MAd CAM-1)) leading to leukocyte
adhesion to the endothelium, and finally immunoglobulin
superfamily platelet endothelial CAM-1 (PECAM-1), respon-
sible for transmigration of leukocytes.46 The complex specific
migration of leukocytes to the target tissue requires a coordi-
nated process of proinflammatory mediators. Proinflamma-
tory cytokines, IL-1α and TNF-α, may induce expression of
proinflammatory chemokines. Chemokines play a major role
in the activation of integrins needed for adhesion of rolling
leukocytes to the vessel endothelium, and this process leads
to leukocyte transmigration to the surrounding tissue, initiat-
ing the inflammatory process.
Immunologic screening
Methods are available to predict the compatibility of donor
tissue to a particular recipient. The greatest value of these
clinical tests is to exclude recipients who would be expected
to manifest a hyperacute rejection to a specific donor organ.
Blood group typing is an important first step in determin-
ing transplant compatibility. An ABO mismatch will result in
certain failure because of preformed antibodies.47 Although it

623
Antiproliferative agents
Table 32.1  Antibody-mediated drugs
Agent
Mechanism
Action
Side-effects
Antilymphocyte
Antilymphocyte
globulin
Antibodies directed against
antigens on lymphocytes
Promotes T-cell clearance through
complement-mediated lysis
Thrombocytopenia, leukopenia, increased
risk of viral reactivation, serum reaction
Antithymocyte
globulin
Antibodies directed against
antigens on thymocytes
Promotes T-cell clearance through
complement-mediated lysis
Thrombocytopenia, leukopenia, increased
risk of viral reactivation, serum reaction
Alemtuzumab
Antibody against CD52
Eliminates T cells by antibody-
dependent cellular cytotoxicity
Thrombocytopenia, leukopenia, increased
risk of viral reactivation, serum reaction
OKT3
Murine monoclonal antibody
directed against the CD3
subunit on human T cells
Eliminates T cells by the
reticuloendothelial system;
blocks cytotoxic activity of
activated T cells
Significant cytokine syndrome, reactivation of
viruses, post-transplantation
lymphoproliferative disease
Anti-IL-2
Daclizumab,
basiliximab
Blocks binding to CD25 (high-
affinity chain of IL-2 receptor)
Limits T-cell expansion; acts only
on activated cells
None
CTLA-4 Ig
Belatacept
Selective T-cell costimulation
blocker binds to CD80 and
CD86 receptors on antigen-
presenting cells (APC)
Blocks the required CD28-
mediated interaction between
APCs and T cells needed to
activate T lymphocytes.
Post-transplant lymphoproliferative disorder,
other malignancies, and serious infections.
Increased risk for developing post-transplant
lymphoproliferative disorder, predominantly
involving the CNS. Recipients without
immunity to Epstein–Barr virus are at a
particularly increased risk
IL-2, interleukin-2.
In all of the transplanted organs including hand and face
transplants, it appears that it is central to prevent allograft
recognition during the peritransplantation period. This is
currently achieved through so-called induction protocols.
Several agents are currently used to protect the transplant
during that period of cytokine excess observed after surgery
(Table 32.2). After the induction agents are used, “mainte-
nance” medications are used to maintain the transplant.
Finally, when ongoing rejection occurs, it is often necessary to
use “rescue” agents to stop ongoing rejection and salvage a
transplant that would otherwise be lost.
Corticosteroids
These agents remain a central tool for both the prevention and
treatment of allograft rejection. Whereas steroids are not
effective as solitary agents to prevent rejection, they have
been shown to improve graft survival in combination with
other agents. When used at high doses, they can also treat
ongoing acute cellular rejection. Despite these uses, steroids
also contribute to the morbidity associated with modern
immunosuppression.
Glucocorticosteroids bind to an intracellular receptor after
nonspecific uptake in the cytoplasm. The receptor–ligand
complex then enters the nucleus, where it acts as a DNA-
binding protein and increases the transcription of several
genes.50 The most important gene is thought to be IκBα, which
binds to and prevents the function of NF-κB (a key proinflam-
matory cytokine that is an important transcription factor for
T-cell activation). Steroids block the production of IL-1 and
TNF-α by antigen-presenting cells. They also block interferon-γ
production by T cells and migration and lysosomal enzyme
release by neutrophils. Steroids also mute the up-regulation
of the MHC and, through their diminution of the inflamma-
tory responses, decrease the degree of costimulation in the
environment. Steroids do not have an impact on the produc-
tion of antibody.
Antiproliferative agents
Azathioprine
This was the first immunosuppressive agent employed in
transplantation and is now largely a historical transplant
medication. Azathioprine undergoes conversion in the liver
to 6-mercaptopurine and then to 6-thioinosine monophos-
phate. These derivatives inhibit DNA synthesis by alkylating
DNA precursors and inducing chromosome breaks through
interference with DNA repair mechanisms. In addition, they
inhibit the conversion of inosine monophosphate (IMP) to
adenosine monophosphate and guanosine monophosphate
(GMP), which depletes the cell of adenosine. The effects of
azathioprine are nonspecific, and it acts not only on dividing
T cells but on all rapidly dividing cells. The primary toxic
effect is on the bone marrow, gut, and liver cells. Azathioprine
is ineffective as a single agent and cannot be used as a rescue
agent. It has been used for maintenance when it is given in
combination with steroids and a calcineurin inhibitor.

624
CHAPTER 32 • Transplantation in plastic surgery
steroids or, more commonly, calcineurin inhibitors (tacrolimus
and cyclosporine).
Calcineurin inhibitors
Cyclosporine
Cyclosporine is a cyclic endecapeptide that was isolated
from the fungus Tolypocladium inflatum gams in 1972.55,56
This drug acts as a T-cell-specific immunosuppressant,
and its mechanism of action is primarily through its
ability to bind to the cytoplasmic protein cyclophilin.55 The
cyclosporine–cyclophilin complex forms a high-affinity bond
with calcineurin–calmodulin complex and blocks the calcium-
dependent phosphorylation and activation of NF-AT. The
interference with NF-AT prevents the subsequent transcription
of the gene encoding IL-2. This process also interrupts other
genes critical for T-cell activation. In addition, cyclosporine
increases transforming growth factor-β transcription, which
appears to down-regulate T-cell activation further, decrease
blood flow to the area, and activate pathways critical to wound
healing.56,57
Mycophenolate mofetil
Mycophenolate mofetil (MMF), which was approved for use
after allograft transplantation in 1995, acts through noncom-
petitive, reversible inhibition of IMP dehydrogenase.51 This
modification improves the bioavailability of mycophenolic
acid. Physiologic purine metabolism requires that GMP be
synthesized for the subsequent production of guanosine tri-
phosphate (GTP) and deoxyguanosine triphosphate (dGTP).
GTP is required for RNA synthesis and dGTP for DNA syn-
thesis. GMP is formed from IMP by IMP dehydrogenase.
MMF prevents a critical step in both RNA and DNA synthesis.
However, MMF does not affect the “salvage pathway” for
GMP production that is present in most cells. This pathway
is not present in lymphocytes, and MMF exploits this differ-
ence and spares most other cells in the body, including neu-
trophils. MMF blocks the proliferative response in both T and
B cells, inhibits antibody formation, and prevents clonal
expansion of cytotoxic T cells.
MMF decreases biopsy-proven rejection and the need for
antilymphocyte agents in rescue therapy compared with
azathioprine.52–54 MMF has replaced azathioprine in clinical
transplantation. However, MMF cannot be used as a sole
immunosuppressive agent and must be paired with either
Table 32.2  Immunosuppressive drugs
Agent
Mechanism
Action
Side-effects
Calcineurin inhibitors
Cyclosporine
Binds to cyclophilin, blocks the NF-AT
transcription factor, inhibits production of
IL-2, and promotes production of TGF-β
Prevents cytokine transcription and
arrests T-cell activation
Nephrotoxicity, hypertension,
neurotoxicity
Tacrolimus
(FK506)
Binds to FK-binding protein, blocks the
NF-AT transcription factor, inhibits
production of IL-2, and promotes
production of TGF-β
Prevents cytokine transcription and
arrests T-cell activation
Nephrotoxicity, neurotoxicity,
diabetogenicity
Antiproliferative agents
Azathioprine
(Imuran)
Inhibits DNA synthesis, interferes with DNA
repair mechanisms, and inhibits
conversion of IMP to AMP and GMP
Blocks the proliferative response (T and
B cells)
Bone marrow suppression,
hepatotoxicity
Mycophenolate
mofetil
Noncompetitive, reversible inhibitor of IMP
dehydrogenase; interrupts production of
GTP and dGTP, prevents critical step in
RNA and DNA synthesis
Blocks the proliferative response (T and
B cells), inhibits antibody formation,
and prevents clonal expansion of
cytotoxic T cells
Gastrointestinal toxicity, bone
marrow suppression
Corticosteroids
Corticosteroids
Binds to intracellular receptor, increases
transcription of gene for IκBα, and
prevents the transcription of NF-κB (a key
activator of proinflammatory cytokines)
Blocks IL-1 and TNF-α production by
antigen-presenting cells, blocks
up-regulation of the MHC, inhibits
production of interferon-γ by T cells
and lysosomal enzymes and
migration by polymorphonuclear cells
Osteonecrosis, osteoporosis,
growth suppression, glucose
intolerance, hypertension,
central nervous system effects
Macrolide inhibitors
Sirolimus
(rapamycin)
Binds to FK-binding protein, impairs signal
transduction by the IL-2 receptor, and
arrests the cell cycle of lymphocytes
Interrupts T-cell activation pathway
Hypertriglyceridemia, bone
marrow suppression
AMP, adenosine monophosphate; dGTP, deoxyguanosine triphosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IL-2, interleukin-2; IMP, inosine
monophosphate; TNF-α, tumor necrosis factor-α; MHC, major histocompatibility complex; TGF-β, transforming growth factor-β;

625
Antilymphocyte preparations
of the drugs bind to the same FK-binding protein, but rapa-
mycin does not affect the calcineurin activity.67,68 Instead, the
interaction of rapamycin and FK-binding protein complex
impairs signal transduction by the IL-2 receptor through its
interaction with a cytoplasmic protein (RAFT-1). In doing so,
the p70 S6 kinase cascade is interrupted and T cells are pre-
vented from entering into the S phase of cell division.69 Thus,
rapamycin is able to interrupt T-cell activation and prolifera-
tion, even in the presence of IL-2.70 Other receptors that are
affected are IL-4, IL-6, and platelet-derived growth factor.
Rapamycin has been shown to prolong allograft survival
in multiple animal models and is being used in several drug
clinical regimens.71 The drug is most commonly used after the
peritransplant period to replace tacrolimus.72 It has also been
applied to the experimental human hand transplantation
patients who have experienced renal toxicity secondary to
tacrolimus.73 This drug has little to no nephrotoxicity. It does,
however, demonstrate some bone marrow toxicity and has
been observed to cause hypertriglyceridemia. Finally, it
appears to interrupt the process of wound healing and caution
should be applied before using it immediately after surgery.
Antilymphocyte preparations
Antilymphocyte/antithymocyte globulin
Antilymphocyte globulin (ATG) is produced by inoculation
of heterologous species with human lymphocytes, collection
of the plasma, and then purification of the IgG fraction. The
result is a polyclonal antibody preparation that contains
antibodies against many of the antigens on human lympho-
cytes. When thymocytes are used as the inoculum instead of
lymphocytes, the product is known as ATG. The most common
ones employed in transplantation are made in the horse
(ATGAM, Pharmacia & Upjohn, Kalamazoo, MI) and in the
rabbit (ATG (Thymoglobulin), SangStat Medical, Fremont,
CA).
The mechanism behind the effectiveness of these drugs is
through the coating of the T cells by the antibodies.74,75 These
coated T cells are then eliminated by complement-mediated
lysis and opsonin-induced phagocytosis. The mere presence
of the antibodies on the surface of the T cell reduces its ability
to express an effective TCR signal. The overall impact of the
antibodies is functionally to remove the primary effector cells
required for acute rejection after transplantation.
These drugs have been employed as induction agents at the
time of transplantation to reduce the possibility that T-cell-
mediated antigen recognition will occur when the graft is in
its most vulnerable state. These drugs are also used as rescue
agents, and their effectiveness is based solely on their ability
to destroy cytotoxic T cells. Most of the side effects are due to
the drug’s heterologous origin and the fact that it can also
bind to other cells. Therefore, one can observe thrombocyto-
penia, anemia, and leukopenia. The most common reaction is
a cytokine release syndrome. Chills and fevers occur in up to
20% of patients. A rash consisting of raised erythematous
wheals on the trunk and neck is seen in 15% of patients. The
use of antilymphocyte drugs has been associated with the
reactivation of viral disease.
The extent of peripheral lymphocyte depletion in the
blood appears to be dose-dependent. Although these agents
The effect of cyclosporine is reversible because it blocks
TCR signal transduction but does not inhibit costimulatory
signals.58 If the drug is withdrawn, the T cell is not anergic but
is again capable of mounting an attack on its target. The effects
of cyclosporine can be overcome with the exogenous admin-
istration of IL-2. This may explain why cyclosporine is not
effective once rejection is ongoing; it is only useful as a main-
tenance agent and is ineffective as a rescue agent.
Cyclosporine also has significant toxicity associated with
its administration. It has significant vasoconstrictor effect
(mediated by transforming growth factor-β) on the proximal
renal arterioles and this decreases renal blood flow by 30%.
Its effects on the kidney can promote fibrosis and hyperkale-
mia and may interfere with the resolution of acute tubular
necrosis. The drug also has neurologic side effects, such as
tremors, paresthesias, headache, depression, confusion, and
seizures. It may also cause hypertrichosis and gingival hyper-
plasia. The use of cyclosporine in solid-organ transplantation
protocols has largely been replaced by tacrolimus.
Tacrolimus
Tacrolimus (FK506), a macrolide produced by Streptomyces
tsukubaensis, was discovered in 1986. Tacrolimus, like cyclo-
sporine, blocks the effects of NF-AT, prevents cytokine tran-
scription, and arrests T-cell activation. The intracellular target
is an immunophilin protein distinct from cyclophilin known
as FK-binding protein.58,59 The effect is additive to that of
cyclosporine, and these drugs cannot be given together
because of the prohibitive toxicity. Tacrolimus also increases
the transcription of transforming growth factor-β and thus
shares both the beneficial and toxic effects seen in the admin-
istration of cyclosporine. It is, however, 100 times more potent
in its inhibition of the production of IL-2 and interferon-γ. The
renal side effects are similar to those with cyclosporine. It has
more pronounced neurologic side effects and a diabetogenic
effect. The cosmetic side-effects are less than those with
cyclosporine. This drug has been proved to be effective as a
maintenance drug for both liver and kidney transplantation.
It has only minimal use as a rescue agent.60
A topical preparation of tacrolimus has recently been
developed and approved for use in atopic dermatitis. Its
mechanism of action and local route of administration render
it an attractive therapeutic alternative for the treatment of
various autoimmune dermatologic conditions and could be of
potential use in CTA. It has also been widely used in clinical
hand and face transplant immunosuppressive protocols for
both maintenance and treatment of rejection.5 There has also
been some evidence that it can be used in graft-versus-host
disease (GvHD).61 The mechanism by which topical tacroli-
mus may be effective in GvHD is the suppression of local
cytokine secretion such as IL-2, interferon-gamma, and TNF-α
in the skin.62 The only adverse events reported in its derma-
tologic applications have been local irritation, pruritus, ery-
thema, and burning.63,64 The majority of these symptoms are
reported to occur when initiating treatment and systemic
effects have not been observed.
Rapamycin
Rapamycin is a macrolide antibiotic derived from Streptomyces
hygroscopicus and is structurally similar to tacrolimus.65,66
However, they antagonize each other’s biologic activity. Both

626
CHAPTER 32 • Transplantation in plastic surgery
of IL-2 receptor.81,82 These agents were designed to have the
same indications for treatment as ATG and OKT3, without the
significant side effects of those agents.
The high-affinity chain on the IL-2 receptor is required for
T-cell expansion and targeting. This receptor offers the advan-
tage that the CD25 receptor is present only on those active T
cells. Theoretically, this agent should affect only those cells
that have been activated against a new allograft. This agent is
also useful in that it does not lead to the activation of the T
cell and therefore potential cytokine release, as is seen with
OKT3. These agents have also had several of the murine por-
tions of the molecule replaced with human IgG, thus eliminat-
ing much of the nonspecific reactions observed in the
heterogeneous antibodies. These agents can be used in the
induction phase, but because IL-2 is needed only in the initial
activation of T cells, it does not appear to be useful to stop
ongoing rejection. Early studies of use as induction agents
demonstrated a lower incidence of acute rejection but no long-
term graft prolongation in both cardiac and renal allografts.83
Currently it is used as induction therapy with two doses
(day 0 and day 4) as part of double- or triple-immunotherapy
regimens in adult renal transplant recipients and appears to
reduce acute rejection episodes without increasing the inci-
dence of biopsy-proven acute rejection than alemtuzumab
induction. Basiliximab is generally associated with a tolerabil-
ity profile that is similar to that reported with placebo, and
better than that reported with ATG.84 The drug does appear
to allow for reduced dosage of corticosteroids or calcineurin
inhibitors, while maintaining adequate immunosuppression,
thereby reducing the potential for adverse effects associated
with these co-administered agents. However, its use as an
induction agent is usually limited to those patients who
cannot tolerate either alemtuzumab or ATG.
Alemtuzumab
Alemtuzumab is an anti-CD52 antibody that has enjoyed
increased use in solid-organ transplantation as a lympho-
depleting induction agent. CD52 is expressed on most T and
B lymphocytes, NK cells, and monocytes. Alemtuzumab
profoundly depletes T cells from peripheral blood for several
months with a somewhat reduced effect on B cells, NK cells,
and monocytes (in descending order).85–89 It has very minimal
effect on CD34+ hematopoietic stem cells. The initial enthusi-
asm for its application in solid-organ transplantation was
based on research by Calne et al., where 33 kidney recipients
were treated with alemtuzumab in combination with low-
dose cyclosporine. These patients were then compared to
the unit’s historical control of patients on standard triple
therapy.90,91 The 5-year survival of these two groups was
similar and this finding led to the initial suggestion that the
use of this agent could lead to “prope” tolerance (graft accep-
tance with reduced immunosuppression).91 However, later
attempts to use the drug alone or in combination with deoxy­
spergualin led to 100% acute rejection, demonstrating that the
drug itself was not tolerogenic. This may be due to the lack
of CD52 expression on plasma cells and poor effect on memory
T cells. Alemtuzumab combined with a single agent for main-
tenance (low-dose calcineurin inhibitors) demonstrated safety
and efficacy, but has an unacceptably high rate (28%) of early
cellular and humoral acute rejection. The drug is currently
used as an induction agent with tacrolimus and MMF. Several
preferentially bind to T cells, they may also bind to B cells,
dendritic cells, and other nonlymphoid cell lines, especially at
high doses. In fact, two pilot studies have demonstrated that
high-dose ATG induction can facilitate monotherapy mainte-
nance immunosuppression in selected patients, with graft and
patient survival comparable to the current standard.76,77 Treat-
ment with ATG has been shown to be associated with both
short- and long-term changes in T-cell populations, generat-
ing altered homeostasis characterized by expansion of specific
T-cell subsets that have been shown to exhibit regulatory
suppressor functions. The use of ATG induction has been
demonstrated to result in a lower incidence of acute rejection
and improved graft survival during the first year after trans-
plantation. However, as has been observed with most induc-
tion agents, patient and graft survival after 20-year follow-up
were not affected.78
OKT3
This is a murine monoclonal antibody that is directed against
the signal transduction subunit on human T cells (CD3).
OKT3 is thought to bind to the CD3 subunit found on all
mature T cells and results in the internalization of the recep-
tor, thus preventing antigen recognition and TCR signal
transduction.79,80 In addition, T-cell opsonization and clear-
ance by the reticuloendothelial system occur. After the admin-
istration of OKT3, there is a rapid decrease in the circulating
CD3+ T cells. There is little or no effect on those cells in the
spleen and lymph nodes or thymus. After several days, there
is a return to T cells that are CD4+ and CD8+ but that do not
express CD3. These “blind” T cells remain incapable of
binding to antigen and interfere with the process of antigen
recognition and generation of cytotoxic T cells. Finally, OKT3
blocks the cytotoxic activity of already activated T cells by an
inappropriate degranulation when the CD3 is bound by
OKT3. This mechanism is central to its effectiveness but also
to one of its most significant side effects.
The administration of OKT3 can lead to a profound
systemic cytokine response that can result in hypotension,
pulmonary edema, and a fatal cardiac myodepression. In
about 2% of patients, this syndrome is manifested as an
aseptic meningeal inflammation. Methylprednisolone must
be administered before the delivery of OKT3 to blunt this
adverse reaction. This syndrome abates with subsequent
doses. OKT3 has been used as a rescue agent to treat acute
renal allograft rejection. OKT3 has also been employed as an
induction agent. The drug is superior to steroids in halting
ongoing rejection. However, it has also been shown to cause
a high viral reactivation rate for cytomegalovirus, Epstein–
Barr virus, and other viruses. It has been associated with high
rates of post-transplantation lymphoproliferative disease.
Due to its association with these significant complications, its
use is extremely limited now. This is especially true after the
release of newer induction agents such as alemtuzumab and
maintenance drugs such as rapamycin.
Anti-IL-2
Two monoclonal antibodies have become available for use in
renal transplantation and have also been employed in some
hand transplantations. Both of these agents (daclizumab and
basiliximab) are directed against CD25, the high-affinity chain

627
Immunologic tolerance
mechanisms for the induction of tolerance could offer the
future plastic and reconstructive surgeon the transplantation
of foreign tissues without the need for prolonged
immunosuppression.
Clonal deletion
Clonal deletion is the process in which T cells that express a
TCR specific for a certain antigen are eliminated. The deletion
of these cells can occur in the thymus (central deletion) or
extrathymically in the peripheral tissues (peripheral deletion).
The thymus is the major site for the generation of immuno-
competent T lymphocytes. T-cell progenitors migrate from the
bone marrow to the thymus, where they undergo a well-
defined pathway of maturation. Once the T cells express their
respective TCRs, they then undergo a process of selection.
During this process, cells with low-affinity TCRs are not
stimulated to progress; this is called positive selection. T cells
in the thymus with a high affinity for self antigen are elimi-
nated by a process called negative selection. When this process
is complete, the remaining T cells should be able to recognize
self and mount a response only when they encounter foreign
antigen. Extrathymic clonal deletion has been described in
several experimental models using exogenous antigens93–95 as
well as self antigens,96–98 demonstrating that elimination of
self-reactive antigens can occur after maturation in the thymus.
This mechanism may ensure tolerance to self antigens not
expressed in the thymus. Several strategies attempt to influ-
ence this process.
The acceptance or tolerance of one’s own tissues first devel-
ops in utero along with an immunologic ability to recognize
foreign tissue. This phenomenon was successfully exploited
by Medawar99 in his original experiments in which strain-
specific neonatal rodents were injected with donor cells and
went on to accept skin allografts. The production of the toler-
ant state in an adult can be achieved experimentally by various
methods. A combination of total body irradiation to remove
mature recipient T cells followed by donor bone marrow infu-
sion before transplantation induces a state of chimerism. (The
term chimera is derived from the Greek mythological figure
composed of parts from different animals.) The chimeric host
then develops an immune system that is tolerant of both donor
and self antigens. A further refinement is the use of total lym-
phoid irradiation; the marrow cavities of long bones are pro-
tected during irradiation, thus producing a state of mixed
chimerism.100 These animals have gone on to accept donor
hearts and kidney allografts. Another method of achieving
transplant tolerance involves intrathymic injection of donor
cells. These cells survive in the immunologically “privileged”
thymus and cause production of maturing T cells that are tol-
erant of the donor alloantigen.101,102 All of these methods take
advantage of the central mechanism of tolerance induction
and rely on the phenomenon of clonal deletion.
Anergy
For a T cell to become optimally activated, it requires a second,
independent costimulatory signal in addition to the primary
signal that is generated through contact between the TCR
and the MHC. When T cells are stimulated in the absence of
these signals, they can become functionally nonresponsive to
repeated stimulation with antigen and are termed anergic.103
groups have used it as their induction agent of choice in clini-
cal hand transplants. However, its use is limited due to a lack
of availability and limited production.
Belatacept (CTLA-4 Ig)
Belatacept, a fusion protein between a modified extracellular
domain of CD152 and human IgG1, is approved for use as a
replacement for tacrolimus in kidney transplantation. Belata-
cept is a selective costimulation blocker and is clinically
indicated as a CNI inhibitor substitute with mycophenolate
mofetil and steroids after renal transplantation. Studies in
murine models have shown synergy between costimulation
blockade and mTOR inhibitors such as rapamycin. Studies
in nonhuman primates have demonstrated that the combina-
tion of belatacept and sirolimus prolongs renal and islet
allograft survival. Clinically, phase III trials have shown
supremacy of belatacept in the conservation of renal func-
tion and other adverse events compared to CNIs. Its clinical
use in VCA transplantation has been limited. There have
been reports of transitioning patients from tacrolimus to
belatacept to preserve renal function. Cendales reported a
case of a hand transplant recipient who developed recurrent
acute rejection with alloantibody formation and concomitant
calcineurin inhibitor nephrotoxicity that appeared to resolve
upon conversion from a maintenance regimen of tacrolimus,
mycophenolate mofetil and steroids to belatacept and siroli-
mus.92 There have also been reports from the Austrian group
that in three out of four patients the addition of belatacept
allowed them to lower the dose of tacrolimus in their drug
regimen.
Immunologic tolerance
The ultimate goal of transplantation science is to make geneti-
cally disparate organs or tissues be accepted and regarded as
self. This would make chronic immunosuppression obsolete
and allow the recipient to maintain an intact immune system
to protect against infections and malignant neoplasms. As
true immunologic tolerance would be “functionally com-
plete”, the life expectancy of the organ would not be limited
by chronic rejection. This section provides an overview of the
various mechanisms of T- and B-cell tolerance and what is
known about their role in models of transplant tolerance.
In the transplantation setting, it appears that T-cell-
dependent immune responses are regarded as the primary
cause of graft rejection. Thus, T-cell tolerance is important to
the generation of tolerance to organ allografts. Mechanisms
of T- and B-cell tolerance can be divided into three broad
categories: clonal deletion, anergy, and suppression. Clonal
deletion is the process whereby T cells with particular
antigen specificity are eliminated from the repertoire. Anergy
is a state in which T cells can recognize a foreign antigen but
are functionally inactive and do not generate an immune
response. Suppression implies the presence of cells that are
capable of actively preventing other T cells from generating
a response. The current thought on the mechanism of sup-
pression is based, in part, on direct action of T-regulatory
cells (T regs). These mechanisms are not mutually exclusive,
and the establishment of tolerance may depend on more
than one of these pathways. The application of these

628
CHAPTER 32 • Transplantation in plastic surgery
the so-called natural (n) T regs that are thought to be gener-
ated intrathymically upon presentation of self antigen by
thymic epithelial cells. The other category is the adaptive or
induced (i) T regs that appear to be produced in the periphery,
after an encounter with either self or foreign antigens. Several
groups have confirmed that mature animal and human T cells
can be converted from CD25− to CD25+ or Foxp3− to Foxp3+
in different experimental settings.30–34 Although both types of
T regs share similarities, nT regs seem to have more stable
expression of Foxp3.35
An additional finding has been that individual populations
of T regs may not only have different origins, but exhibit
significant plasticity in the expression of their phenotype
(much like TH cells) depending on the cytokine milieu. Recent
rodent data have shown that, after ex vivo manipulation of
CD4+ CD25+ T regs with either Th1 or Th2 cytokines, the
function of the cells can be quite different.36 In certain circum-
stances these T regs (CD25+Foxp3+) can not only trigger the
expansion of Th17-producing T cells but can also differentiate
themselves into Th17 T cells in vitro upon stimulation with
allogeneic antigen-presenting cells.37,38,118
Several articles have reported a high proportion of circulat-
ing and intragraft T regs in tolerant/stable patients in renal
as well as liver and lung transplantation. In contrast, recipients
with chronic rejection had significantly fewer T regs and
lower levels of Foxp3 transcripts than clinically tolerant
patients and healthy individuals. Mechanistic studies in renal
transplant recipients confirmed that donor hyporesponsive-
ness was abrogated by depletion of CD4+ CD25+ high T cells.
Thus, a technique to produce T regs could increase the dura-
bility of tolerance and perhaps be employed along with other
tolerance induction techniques.
Transplantation in plastic surgery
Skin
Skin autograft
Autologous skin grafts can be of either full or partial thick-
ness. The full-thickness skin graft gives an excellent cosmetic
result with limited graft contraction but has the disadvan-
tage of unreliable graft “take”. The amount of full-thickness
skin graft is also limited by donor site availability. In cases in
which large areas are to be covered, split-thickness skin
grafting is used and is the most commonly practiced form of
tissue transplantation in plastic surgery. It has the advantage
of large available donor areas and better graft take but the
disadvantage of increased graft contraction. Expansion of
the split-thickness skin graft by meshing with expansion
ratios from 1 : 1.5 to 1 : 9 is both useful and often essential in
large burns.
Donor sites for split-thickness skin graft harvest may be
limited in patients with extensive burns. This lack of available
tissue has spurred the development of alternatives to conven-
tional skin graft. Keratinocytes can be grown in culture with
the ability to expand the available tissue 10 000-fold.119 This
technique has been applied in the treatment of large thermal
injuries as well as leg ulcers and other benign conditions.120
The reported disadvantages with cultured keratinocytes are
Two major costimulatory interactions that take place between
a T cell and antigen-presenting cell involve CD28/B7 and
CD40L/CD40 pathways.104,105 There has been considerable
interest recently in trying to block these pathways. Anergy is
not automatically maintained once it is induced, and the
continual presence of antigen has been shown to be required
to maintain tolerance.106,107 Tolerance relying on anergy may
also be a precarious state. It can be broken by infection and
inflammation.108,109
The blockade of these second signals uses antibodies
(CD40, CTLA4) to specific receptors (CD40R, B27) to induce
a peripheral form of tolerance. The concept that the presenta-
tion of antigen in certain situations could down-regulate the
immune system is not new. Before the discovery of these
receptors, previous investigators had noted that donor-specific
blood transfusions appeared to increase graft survival, theo-
retically by presenting MHC antigens in a limited fashion and
inducing a state of T-cell anergy rather than activation.110 The
interruption of the CD40 and CD28 pathways (costimulatory
blockade) at the time of transplantation has been demon-
strated to induce a state of tolerance in several rodent models
without any significant infectious or malignant complications.
However, the application to the primate model has not repli-
cated these results and has demonstrated only prolongation
of allograft survival rather than tolerance. Several modifica-
tions of this technique are under study and may lead to a
longer-lasting state of donor-specific T-cell anergy. Other
methods of peripheral tolerance induction include donor
antigen-presenting cell depletion or modification and anti-
CD4 antibody to block TH-cell function.111 These peripheral
methods of tolerance induction have not been as effective as
the central mechanisms.
Immune regulation by regulatory cells
A role for active suppression in inducing and maintaining
tolerance had been suggested by a number of studies.
However, previously there had been an inability to propagate
these cells in vitro or to identify these cells in vivo. This
made it difficult to identify the mechanism involved. Thus,
the mechanism of suppression remained controversial, despite
a number of transplantation models that provided functional
evidence for the existence of such cells.112–114 Significant
progress has been achieved in the characterization of
these suppressor/regulatory cells with the identification of a
T-cell population that coexpresses CD4 and CD25 surface
antigens.115
These CD4+ CD25+ T cells occur naturally in the thymus
and represent a functionally distinct subpopulation of T cells.
These cells have been characterized as a suppressive T-cell
population that promotes tolerance to self and foreign
antigens.116 In 2003, three independent groups showed that
Forkhead box protein 3 (Foxp3), a nuclear transcription factor
defective in the multisystemic autoimmune disease IPEX
(immune dysregulation, polyendocrinopathy, enteropathy,
X-linked syndrome),117 was expressed in CD4+ CD25+ T
regs.19–21 Foxp3 was shown to correlate with suppressive activ-
ity and appears to regulate the expression of several cell
surface molecules previously used to identify T regs, such as
CTLA-4, GITR, and CD25 itself.20
T regs can also be defined by their origin and are currently
divided into two physiologically distinct groups. There are

629
Transplantation in plastic surgery
covering and will survive with immunosuppressive drugs.139
Growth in culture is possible pre-emptively in burn treatment,
but skin allografts are susceptible to rejection in addition to
the problems associated with cultured autografts.
Skin xenograft
Porcine xenograft has been used as a temporary dressing in
large burns with seeding of autologous grafts beneath it.140
The application of xenogeneic dermis has also been found
valuable in preparing a wound for subsequent grafting by
stimulation of granulation tissue formation. The acellular
artificial skin described by Burke et al.125 uses a bovine colla-
gen dermis that recipient fibroblasts repopulate. Xenogeneic
tissue has limited uses in skin grafting because its cellular
components are susceptible to hyperacute rejection.
Bone
Bone autograft
A series of basic histologic events follows transplantation of
a bone autograft.141 After transplantation, the graft is sur-
rounded by hematoma; the inflammatory cascade follows
in which infiltration of inflammatory cells is followed by
ingrowth of new vessels with removal and replacement of any
dead or necrotic tissue. Nonvascularized grafts undergo
necrosis, most of the osteocytes in the graft die, and only those
on the surface that re-establish blood supply survive. The
remainder of the graft is infiltrated by blood vessels from the
recipient site and is repopulated by recipient osteocyte mes-
enchymal stem cells. Vascular ingrowth in cortical bone occurs
through pre-existing haversian canals. There is an initial
increase in osteoclast resorption activity, which increases the
porosity and decreases the strength of the graft. Cancellous
grafts are more rapidly revascularized by virtue of their open
structure within 2–3 days. By comparison, revascularization
of cortical grafts may take up to 2 months. The process in
which vascular tissue invades the graft, bringing with it
osteoblasts that deposit new bone, has been termed creeping
substitution. Cortical bone shows incomplete resorption of
necrotic bone, and the final graft mixture of living and dead
bone does not approach the strength of a cancellous graft.141
Vascularized bone graft obviates the reparative phase of a
nonvascularized graft and does not require a well-vascularized
recipient bed. Biomechanically, vascularized bone grafts are
superior to nonvascularized grafts.142
Reconstruction of larger bone defects is limited by available
autologous donor sites. An alternative being investigated
experimentally is that of autologous osteocytes expanded in
culture and grown in the recipient on polymer scaffolds.31,143
Bone allograft
The advent of well-organized tissue banks and improved
methods of bone graft sterilization and preservation have
allowed the clinical use of large bone allografts.144–147 The use
of frozen bone allograft has become a common practice for
the reconstruction of long-bone defects, with an estimated
annual volume of more than 200 000 procedures in the US.148
MacKewen is credited with the first clinical use of allograft
bone in 1881, followed by Lexer, Parrish, and others.141,149–152
Few if any of the donor cells in the nonvascularized bone graft
that they are more sensitive to bacterial contamination than
are split-thickness grafts, and take has been reported to be
poorer in comparison to meshed graft.121 They also blister
spontaneously, are more susceptible to minor trauma, and
contract more than do split-thickness skin grafts.122 These
effects are related to a poorly developed dermis–epidermis
junction.123 The lack of a dermal component in these autolo-
gous grafts was overcome by a combination of cultured
autologous keratinocytes and allogeneic dermis.124 The tech-
nique has had favorable reports in patients with large burns,
but the problem of an allogeneic dermis remains. Develop-
ment of an acellular or “artificial” skin (Integra) consisting
of dermal components, collagen, and a glycosaminoglycan
overlaid with a sheet of Silastic addressed this antigenic
problem.125 A disadvantage of this approach is the need to
skin graft the “dermis” after removal of the outer Silastic
dressing. This has been superseded by seeding the graft with
keratinocytes at the time of initial application.126
A skin substitute containing allogeneic or xenogeneic
structural proteins and ground substance seeded with autolo-
gous cells has also been described; it is composed of cultured
autologous fibroblasts populating the dermis and cultured
autologous keratinocytes covering the dermis.127 These
collagen gel dressings share the disadvantage of autologous
cell culture in that cells require time in culture for expansion
to usable numbers. An acellular dermal allograft available
commercially is AlloDerm (LifeCell, Branchburg, NJ). A
tissue-engineered living allogeneic dermal construct, Derma-
graft (Advanced Tissue Sciences, La Jolla, CA) consists of
human neonatal dermal fibroblasts seeded on to a synthetic
mesh.128 It has compared favorably with skin allograft as a
temporary cover for severe burn wounds.129 Another substi-
tute is Graftskin (Organogenesis, Canton, MA), which is
composed of a type I bovine collagen matrix seeded with
allogeneic human fibroblasts and overlaid with allogeneic
human keratinocytes.130
Skin allograft
Skin allografts have been found to be beneficial in large burns
either in combination with autograft or in isolation.131–135
Techniques such as use of widely meshed autologous split-
thickness skin grafts with a meshed allograft overlay have
been shown to have improved healing in comparison to
autologous mesh alone. The availability of skin allografts has
increased with the formation of regional tissue banks. Alloge-
neic skin may be frozen and banked in a manner that allows
it to remain viable for a protracted period. Preservation with
glycerol reduces the antigenicity of skin allografts and pro-
longs their survival.136 Glycerol-treated grafts have been used
in burn centers as coverage for burn wounds before autograft-
ing137 or as composite grafts overlying widely meshed auto-
grafts.133 However, the use of these grafts has been reported
to lead to the production of antibodies that may inhibit the
possibility of future VCA.
Factors that limit widespread use are that harvesting
and banking services are not uniformly available, demand
outstrips supply, and there is a small but significant risk of
disease transmission. Cytomegalovirus infection, hepatitis,
and human immunodeficiency virus infection have been
reported in burn patients after cadaveric skin use.138 Cultured
allogeneic keratinocytes have also been used as a temporary

630
CHAPTER 32 • Transplantation in plastic surgery
delivery of autologous cartilage by needle, transcutaneously,
or arthroscopically.175–177
Cartilage allograft
Chondrocytes express HLA antigens on their surface and are
immunogenic.153 The matrix is only weakly antigenic.178 Surgi-
cal scoring or dicing with resultant exposure of allogeneic
cells has been shown to hasten reabsorption of allogeneic
cartilage.179 Cartilage allografts have been used for applica-
tions similar to those of autologous cartilage.180 Allogeneic
cartilage can be either preserved or fresh. Preserved cartilage
has the advantage of a more abundant supply without the risk
of infection that is associated with the use of fresh cartilage.181–183
Cartilage allograft, usually with irradiation pretreatment, has
been used for volume augmentation in the facial skeleton.
Despite initial good results in a large number of patients,183
long-term data suggest a high rate of resorption.184 Whether
this is immunologically based or because preserved grafts
tend to contain no viable cells is a matter for debate.185 It has
also been noted that smaller grafts are less susceptible than
larger ones to graft volume loss.
Cartilage xenograft
Bovine-derived cartilage xenografts are susceptible to xeno-
geneic mechanisms of rejection, which results in a generally
poorer outcome in comparison to either allogeneic or auto­
genous cartilage grafts. Attempts to modify these xenogeneic
responses by altering the graft’s immunologic stereotactic
structure have been reported as being beneficial.186
Nerve
Nerve autograft
The best clinical outcome after nerve transection is achieved
with primary repair. Extensive injuries with a nerve gap
require a nerve graft to achieve nerve repair without tension.
The nerve graft undergoes the same degenerative process as
in the distal recipient nerve after division.187 What remains of
the nerve graft is a myelin sheath with Schwann cells that act
as a biologic conduit for the regenerating axons. The most
common type of nerve graft is the interfascicular nerve graft,
which joins fascicular groups to their distal matching group
with an interposition nerve graft.188 Other types in modern
practice are fascicular nerve grafts (limited by matching
proximal to distal fascicle) and vascularized nerve grafts,
thought theoretically to be of advantage, although not of
proven benefit clinically.189 Other “conduits” have been used
as nerve grafts,190 such as silicone tubes seeded with Schwann
cells, autologous vein, freeze-fractured autologous muscle,
and pH tubes.191 Artificial conduits have demonstrated
improved outcome when they have been seeded with autolo-
gous Schwann cells. None of the conduits to date has been
found to be superior to nerve autograft.
Nerve allograft
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 experimentally with immunosuppressive
survive. The remaining bone acts as scaffold for ingrowth of
recipient mesenchymal stem cells (osteocyte precursors) that
repopulate the donor scaffold by creeping substitution. The
larger graft acts as a mechanical spacer; because of slow
union, long-term fixation is required, and as a result, the graft
is susceptible to stress fracture and loosening of metal fixation
devices. Large joint replacement has been in clinical practice
for some time with mixed results. Parrish reported 50% col-
lapse with use of frozen whole bone ends in 21 cases.151 Mixed
results with use of large or smaller shell grafts for joint
resurfacing or replacement after surgical excision have
been reported.153–155 In craniofacial surgery, freeze-dried bone
allografts have been used in midface advancements.156 The
infection rate was high, at 22%, but osteotomies healed in all
patients. Bone allograft with autogenous bone chips has been
reported in mandibular reconstruction.157,158 In hand surgery,
bone allograft has been used to reconstruct defects after
benign tumor removal and for traumatic or congenital
defects.159,160 No major complications were reported, such as
infections, fractures, or nonunion.
Vascularized allogeneic bone is susceptible to immunologic
rejection.161–164 The humoral and cellular response generated
has a time sequence similar to that generated by any
other allogeneic tissue.12 Although individual bone cells
express antigens, the predominant immunogenic cell in a
bone allograft is thought to be bone marrow-derived.150
Removal of marrow as in irradiation or by replacement with
recipient marrow has been shown experimentally to prolong
allograft survival.165,166 There has been a limited series of
vascularized clinical allogeneic bone transplants (knee trans-
plants) performed first under single-agent (cyclosporine)
immunosuppression and later employing triple-drug immu-
nosuppression.167,168 All of these grafts were lost within the
first 56 months, regardless of the immunosuppression chosen.
One confounding factor may be the addition of a vascularized
skin paddle for immune monitoring that may actually increase
the immunogenicity of the transplant.
Cartilage
Autologous cartilage
Cartilage is composed of chondrocytes within lacunae dis-
persed throughout a water-laden matrix. There are histologi-
cally three types: hyaline cartilage, elastic cartilage, and
fibrocartilage. The matrix is composed predominantly of
proteoglycans and type II collagen. Cartilage has no blood
supply and relies on diffusion of nutrients and oxygen through
the matrix. Chondrocytes, in contrast to osteocytes, have little
reparative ability and heal by forming fibrous scar tissue.169
The viscoelastic properties of the matrix provide cartilage
with a “memory” in that it returns to its original shape after
deformation; the variable water content in matrix causes a
balanced tension within it and thus maintains its three-
dimensional shape.
Cartilage autograft is used regularly for nasal, auricular,
craniofacial, and joint surface reconstruction.170–172 There are
limited potential donor sites. Development of experimental
tissue-engineering techniques has allowed the expansion of
chondrocytes in culture to increase their numbers. These cells
are seeded on to biodegradable polymers to form new autolo-
gous cartilage.31,143,173,174 Injectable polymer systems allow

631
Transplantation in plastic surgery
host immunosuppression to prevent allograft rejection. The
potential adverse effects of indefinite, multiple-agent immu-
nosuppression are difficult to justify in the opinions of many
for a surgical procedure aimed at improving quality of life.14,213
This debate over the risk–benefit balance has continued since
the first successful human hand transplantation. However,
both the proponents and critics of the current transplants
agree that significant reduction of host immunosuppression,
and particularly tolerance induction to the allografts, would
help achieve widespread clinical application of composite
tissue allografts.
Experimental limb transplantation
Limb allograft transplantation is possible experimentally with
different immunosuppressive regimens.205–207,209,214–222 Immune
modulation techniques that decrease the antigenicity of spe-
cific components of a limb allograft were shown to prolong
survival.166 Although sporadic incidents of tolerance have
been reported after cessation of immunosuppressants,216,223
long-term immunosuppression was generally necessary to
prevent allograft rejection. Combination therapy with cyclo-
sporine and MMF was more effective than monotherapy.224
Although rat models provide important information on limb
allograft transplantation, the rodent immune system is funda-
mentally different from that of the human. A large animal
model such as a canine, pig, or primate offers a much closer
analogy to the human immune system.
Ustuner et al. reported transplantation of a radial forelimb
osteomyocutaneous flap between size-matched outbred
swine with use of a daily cyclosporine, MMF, and predni-
sone oral regimen.223 Of the eight swine, two sustained
severe rejection, three demonstrated mild to moderate rejec-
tion, and three were free of rejection at the termination of the
experiment at 90 days. No drug toxicity was evident in
serum hematologic and chemical parameters of immunosup-
pressed animals. The Louisville group also examined the use
of FK506, MMF, and prednisone in the same swine model.225
Five of nine animals that survived to the study end at 90
days were noted to be free of rejection. However, this combi-
nation of immunosuppressants resulted in significant mor-
tality and morbidity, including abscesses, diarrhea, weight
loss, and pneumonia.
Lee et al. sought to achieve host tolerance to musculoskel-
etal allografts through matching of the MHC antigens between
donor and host swine with only a 12-day course of cyclospo-
rine.226 Allografts from MHC-mismatched donors treated
with cyclosporine and allografts from MHC-matched (minor
antigen-mismatched) donors not treated with cyclosporine
were rejected. However, allografts from MHC-matched
donors treated with 12 days of cyclosporine showed no evi-
dence of rejection until sacrifice up to 47 weeks after trans-
plantation. Thus, genetic matching may alleviate the need for
immunosuppression after limb transplantation. MHC match-
ing can be extended beyond family members, for example, as
the National Bone Marrow Registry exists to match MHC of
unrelated individuals.
More recently, Kuo et al. demonstrated that the use of
mesenchymal stem cells combined with bone marrow trans-
plantation, irradiation, and short-term immunosuppressant
therapy could prolong CTA survival (>200 days) in a swine
hind-limb model.227 The authors suggested that the regulatory
drugs,192,193 and immunosuppressed axons will traverse the
allogeneic graft in rodents194,195 and nonhuman primates.196
Immunosuppression needs to be administered only while
the recipient axons traverse the allograft and can then
be terminated.197–199 Mackinnon et al. reported a series of 7
patients who underwent nerve allografting in the upper and
lower extremities.190,200 Immunosuppression was stopped 6
months after nerve regeneration across the allografts. All but
one patient demonstrated return of motor and sensory
functions.
Limb and composite tissues
Microvascular autogenous tissue transfer is a well-established
reconstructive modality. Available donor sites limit the autolo-
gous transplants of tissue. In addition these donor sites can
be associated with potential morbidity. The ability to use
allogeneic limb or vascularized composite tissues such as
skin, subcutaneous tissues, muscle, bone, blood vessel, and
nerve has greatly expanded the realm of reconstructive
surgery. Extensive skeletal and soft-tissue defects or even
whole limbs have been replaced. However, nonautogenous
tissue is susceptible to immunologically mediated rejection
with subsequent graft loss, and prolonged immunosuppres-
sion is the only way at present to attain long-term allograft
survival. To make composite tissue transplantation clinically
feasible, consideration should be given to its technical, func-
tional, and immunologic aspects.
Technical considerations
Transplantation of vascularized limb or composite tissues was
made possible by the microsurgical techniques first developed
by Carrel and Guthrie in 1906.201,202 Microvascular anastomo-
ses and revascularization have become routine practice in
large centers, with success rates in excess of 90%.203,204 In
contrast to acute traumatic cases, such as replantation, alloge-
neic transplantation has been performed in elective settings
after appropriate preparation, such as preoperative angiogra-
phy and donor selection. The operative techniques are based
on the current advances in bone, tendon, and nerve repairs.
Functional considerations
Normal wound healing and bone growth occur in transplanted
composite tissue allografts after experimental transplantation
in various animal models.26,205 Return of neuromuscular func-
tion has been observed in limb allografts of animals treated
with immunosuppression,206,207 including those in the pri-
mates,208–210 while in clinical hand transplants both motor and
sensory recovery have been reported.5,211,212 Thus, functional
recovery after allogeneic transplantation appears to follow the
same principles as in nontransplant situations and is influ-
enced by the recipient’s age, systemic factors, and associated
local injuries.
Immunologic considerations
A limb or vascularized composite allograft consists of multiple
discrete tissue components, such as skin, subcutaneous tissue,
muscle, and bone, and each tissue has been shown to be
strongly antigenic.106 Both animal data and the current clinical
human experience have confirmed the need for significant

632
CHAPTER 32 • Transplantation in plastic surgery
measurement of success, the restoration of the patient’s well-
being and sense of self must also be considered in the evalu-
ation of hand transplantation.
The major issues in hand transplantation are the need for
maintenance immunosuppression and the evaluation of the
functional outcomes of the transplants.236,237 There are well-
known risks to the transplant recipient related to the use of
chronic immunosuppression. These include complications
such as an increased susceptibility to opportunistic infections,
renal dysfunction related to the use of calcineurin inhibitor-
based medications (tacrolimus and cyclosporine), and an
increased incidence of malignancies. In addition, despite the
use of modern immunosuppression regimens, the majority of
the transplants experience episodes of acute rejection and will
likely face chronic rejection. The functional outcomes have
been, for the most part, favorable but the current challenge
remains to improve nerve recovery and the restoration of
function of the intrinsic muscles of the hand.
Immunosuppression and transplant survival
The emergence of hand transplantations and the field of
reconstructive transplantation have not corresponded to any
recent breakthrough in transplantation immunology. It is clear
from the 1-year survival data of such highly antigenic trans-
plants as the lung and intestine that the current potent
immunosuppressant drugs can prevent the fulminant rejec-
tion of even highly antigenic tissues, as long as sufficiently
high doses of different agents are used.238,239 This has been
replicated in the hand transplantation literature as there has
been an excellent 1-year survival of the transplants.5 Thus, the
critical issue continues to be how much immunosuppression,
and lifelong morbidity, can be justified for a nonlife-saving
procedure.
There is significant variability in medications employed to
maintain the hand transplants, making it difficult to conclude
the superiority of one immunosuppressive regimen over
another. This type of conclusive evidence will only be derived
from prospective, randomized clinical trials. Therefore, as this
technique expands, it will be important to organize multi-
center trials to determine the best practice for the use of
immunosuppression after hand transplantation.
Currently, the majority of the transplant programs have
employed the use of an induction agent such as IL-2 recep-
tor blocker (basiliximab), ATG, or the anti-CD52 monoclonal
antibody (alemtuzumab). There was an initial trend towards
using more anti-CD52 monoclonal antibody in hand trans-
plant patients but the use of this drug has decreased more
recently.240 The Louisville group initially used the IL-2 recep-
tor blocker (basiliximab) on its first 2 patients as the sole
induction agent but then switched to alemtuzumab on all
subsequent patients,211 while the Lyons group relied solely
on ATG on all its patients.212 More recently, groups at the
Johns Hopkins University and the University of Pittsburgh
have implemented a program to move beyond the current
three-drug regimen. They have employed alemtuzumab
induction therapy as an integral part of their “Pittsburgh/
Johns Hopkins University protocol” that uses donor bone
marrow infusion in combination with tacrolimus monother-
apy in an attempt to reduce the amount of chronic immuno-
suppression needed and thereby improve the risk–benefit
balance.
activity of the mesenchymal stem cells might be contributing
to the prolongation seen in this model.
The primate model offers the closest imitation to human
limb transplantation in anatomy and immune system. In the
1980s, four studies of limb allograft transplantation were
performed on nonhuman primates.209,210,222,228 All of the studies
involved the transplantation of a hand and use of high-dose
cyclosporine and steroids. Many of the animals suffered
multiple infectious complications, with some succumbing
to fatal malignant neoplasms resulting from high levels of
immunosuppression. Nonetheless, few primates demon-
strated prolonged survival of their allografts. These studies
confirmed the existing rodent and canine data that cyclospo-
rine monotherapy is ineffective in preventing limb allograft
rejection, even at toxic doses. Few allografts survived long
enough for functional recovery to be ascertained. More
recently, Barth et al. performed heterotopic transplants of
composite facial subunits consisting of skin, muscle, and bone
in mismatched Cynomolgus macaques.229 They attempted to
use high-dose tacrolimus monotherapy via continuous intra-
venous infusion for 28 days, which was then tapered to daily
intramuscular doses. They had initially hoped that this limited
course of high-dose tacrolimus would lead to tolerance, as
had been observed in the swine kidney model. Although this
protocol of tacrolimus monotherapy did provide prolonged
rejection-free survival of the allografts, it was associated with
the development of a high frequency of donor-derived post-
transplant lymphoproliferative disorder tumors. No study
has been performed in primates with combination immuno-
suppressant therapy. The application of such a regimen could
provide insight into nerve regeneration, bone healing, and
ultimate recovery of function. Cendales’s group examined the
possibility of using belatacept in combination with tacrolimus
in a primate model of hand transplantation. Compared to
tacrolimus, the addition of belatacept improved rejection-free
allograft survival.230 They also found that when they combined
belatacept with rapamycin there was unacceptably high rates
of wound failure in skin-containing transplants.
Hand transplantation
Currently, clinical hand transplantation remains an experi-
mental procedure, and the long-term outcomes of this innova-
tive procedure are still being determined. In the current era
of immunosuppression, there are 107 known transplanted
hand/upper extremities in 72 patients (Table 32.3).5,11,211,212,231–235
The results thus far have demonstrated that hand transplanta-
tion is technically feasible and the outcomes are promising,
with patients reporting varying degrees of return of function.
The support for the application of hand transplantation
from hand surgeons has been strongest for those patients who
have lost both hands.14 While most programs continue to
perform transplants under their local institutional review
board guidelines, several programs have proposed bilateral
hand transplantation as the standard of care for bilateral
amputation but no center has performed a transplant without
an IRB protocol. The support for unilateral transplantation
has been much lower from the surgical community. However,
patients who have undergone unilateral hand transplants
have reported the restoration of self as well as return of func-
tion. Thus, while function is a critical outcome for the

633
Hand transplantation
nonlife-saving transplant. Currently, there is some variation
in the tools that are employed to quantify the function of the
hand transplant. While the Louisville group has reported
much of the functional outcomes in publications based on the
Carroll test (a well-validated test that evaluates the patient’s
ability to perform activities of daily life that involve the upper
limb),242 the International Registry on Hand and Composite
Tissue Transplantation bases its functional outcomes on its
own Hand Transplantation Score System (HTSS).5,211 This
evaluates six aspects of the hand transplant: (1) appearance
(15 points); (2) sensibility (20 points); (3) motility (20 points);
(4) psychological and social acceptance (15 points); (5) daily
activities and work status (15 points); and (6) patient satisfac-
tion (15 points). A total result of 81–100 points is graded as an
excellent outcome, 61–80 as good, 31–60 as fair, and 0–30 as
poor. The University of Pittsburgh bases its evaluation of
patients on measurement of active range of motion, passive
range of motion, grip strength, pinch strength, and two-point
discrimination. They also use the Semmes–Weinstein evalua-
tion to document the sensory return of the transplants.
Early results from this group show that all their patients
The most common maintenance immunosuppressive
regimen used in hand transplantation has been a continuous
administration of low-dose steroid with tacrolimus, and MMF.
However, over time several teams have changed from tacroli-
mus to sirolimus treatment to avoid the side effects, such as
hyperglycemia or renal insufficiency.5 In some cases, the teams
attempted to decrease the immunosuppressive medications
and wean or eliminate steroids from the regimes. However,
while such strategies have been successful in the renal trans-
plant literature, in these hand transplants evidence of myointi-
mal hyperplasia has been noted. In addition, one of the hand
transplants in Louisville was lost due to what appeared to be
chronic rejection after being maintained on reduced immuno-
suppression protocol.231,241 Thus, it may not be possible simply
to transfer protocols that have demonstrated results in renal
transplantation directly to hand transplantation.
Measuring outcomes in hand transplantation
The accurate evaluation of the functional outcome of the hand
transplant patient is critical to determining the value of this
Table 32.3  Upper extremity transplant performed worldwide
Center (country)
Unilateral Tx
Bilateral Tx
Total limbs Tx
Total limb Tx lost
Mortalities
Melbourne (Australia)
1
1
Innsbruck (Austria)
1
4
9
Brussels (Belgium)
1
1
Six centers (China)
9
3
15
7
Lyon (France)
1
5
11
1
Paris (France)
1
2
2
1
Munich (Germany)
1
2
Tehran (Iran)
1
1
Milan (Italy)
3
3
Monza (Italy)
1
2
Selayang (Malaysia)
1
1
Mexico City (Mexico)
2
4
2
1
Wroclaw (Poland)
5
1
7
1
Madrid (Spain)
1
2
Valencia (Spain)
3
6
Ankara (Turkey)
1
2
2
1
Antalya (Turkey)
3
6
2
1
Leeds (United Kingdom)
1
1
Brigham and Women’s Hospital (USA)
2
4
2
Emory (USA)
1
1
3
2
University of Pittsburgh/Johns Hopkins (USA)
2
4
10
2
Massachusetts General Hospital (USA)
1
1
University of Louisville (USA)
7
1
9
1
UCLA (USA)
1
1
1
University of Pennsylvania (USA)
1
2
Wilford Hall, Medical Center (USA)
1
1
Totals
37
35
107
25
4

634
CHAPTER 32 • Transplantation in plastic surgery
first patient was 3 years out at the time of publication and has
demonstrated total active motion of fingers equal to 63% of
that of his unaffected hand. His DASH score was reported as
95 and the patient returned to work 20 months after the
transplant. The second patient was only 6 months post-
transplant and scored 85 points on the DASH questionnaire.
The surgeons reported that the Semmes–Weinstein monofila-
ment test had documented 15 mm two-point discrimination
and the transplanted hand grip strength reached 4 kg. This
patient had also returned to a full-time job.
The Lyon group documented the late results of their two
bilateral hand transplant patients.212,244 Both patients have
recovered pain and cold sensations, without dysesthesia or
cold intolerance. The first recipient, 6 years after transplanta-
tion when the paper was published, had a Semmes–Weinstein
test that demonstrated sensitivity recovery on the right hand
using 2.83–3.61 monofilaments and on the left hand using
monofilaments between 3.22 and 4.08. The average two-point
discrimination test was 6 mm on the right hand and 9 mm on
the left hand. In contrast, the second patient’s Semmes–
Weinstein test demonstrated sensitivity recovery on the right
side using 3.22–3.61 monofilaments and on the left side using
monofilaments between 3.22 and 3.84. However, muscle
strength was diminished in both patients. The first patient had
bimanual grip strength of 12 kg and the second patient’s grip
strength was 4 kg on the right side and 8 kg on the left side.
While the authors from Lyon comment that manual dexter-
ity evaluated using the Minnesota and Carroll test demon-
strated a normal capacity for reaching, grasping, moving,
positioning, and turning the objects, they did not provide
scores for these tests. They did comment that the first recipient
continued to have impairment to lateral pinch and bimanual
grasp. The patients were, according to the authors, able
to perform the majority of daily activities by the first year after
transplantation. One of the two patients had returned to
work.
Finally, the Innsbruck group has published an 8-year
follow-up after hand transplantation.245 One of the most sig-
nificant findings from this group is that patients can continue
to observe improvement of their function and sensation even
at years 4 and 5 after transplant. Their first patient demon-
strated excellent recovery after bilateral hand transplantation.
Eight years after transplantation, hand function in this patient
was outstanding. He is able to use his hands symmetrically,
performing all activities of daily life. The current DASH score
is 34. The second patient was a forearm transplant who
has experienced continuous improvement of motor function
during the first 3 years and, according to the authors, has
satisfactory hand function. The patient noted that the hand
function is superior to that he had achieved with myoelectric
prostheses. While the patient has noted recovery of hot and
cold discrimination (at 6 months after transplantation), his
overall sensitivity remains poor with no detectable two-point
discrimination. Grip strength measured 6.8 kg on the right
side and 5.5 kg on the left side. However, compared with
results after hand transplantation, fine motor skills were
slightly inferior in our forearm transplant patient. The third
patient was still in the process of undergoing intensive out-
patient therapy at the time of the publication.
The world experience in hand transplantation demonstrates
the clinical utility of this emerging technique. However, there
are many questions that are currently unanswered. These
demonstrate sustained improvements in motor function and
sensory return correlating with the time after transplantation
and level of amputation.
All of the hand transplantation programs have used the
Disabilities of the Arm, Shoulder and Hand (DASH) score to
evaluate patients post-transplant.243 The DASH Outcome
Measure is a 30-item self-report questionnaire designed to
measure physical function and symptoms in people with any
of several musculoskeletal disorders of the upper limb. The
tool is a single reliable instrument that can be used to assess
any or all joints in the upper extremity.
The longest follow-up available is from the second hand
transplant performed by the group in Louisville; the patient
is now more than 18 years postoperative with a functioning
hand. In a recent article, the group in Louisville reported
detailed outcomes of the first two American hand transplant
recipients at 8 and 6 years post-transplantation.211,231 Both
patients have allograft survival, with improvements in intrin-
sic muscle activity, total active motion, and return of functional
grip, pinch strength, and sensibility. The latest Carroll test
scores, which measure patients’ ability to perform tasks
requiring a combination of mobility, motor function, and
sensation, are fair for patient 1 (72/99) and fair for patient 2
(55/99). These Carroll test scores exceed the expected results
of 20–30 of 99 that would be achieved with a prosthetic hand.
The first patient’s Semmes–Weinstein monofilament sensation
testing is in the normal range for all fingertips, and the patient
has shown improvement in both static two-point discrimina-
tion and moving two-point discrimination over previous
testing. Touch localization, stereognosis, and temperature and
vibration sensation have also returned. The second patient
has not demonstrated a similar return of sensation through
year 6; however, in 2008, his protective sensation was noted
to have returned. In a more recent update they reported the
results of their third patient in which they stated the Carroll
score was 57 at the yearly checkup. The range of motion with
active digital motion was approximately 45% of normal.
Sensory evaluation showed advancement of Tinel’s sign to
fingertips, diminished protective function, and light touch
localization in the index, ring, and small fingers only.
The International Registry reported that, based on the
HTSS scale, the majority of patients demonstrated good
results from the hand transplant procedure.5 They noted that
from a functional point of view there was good recovery in
the majority of the transplanted hands. However, the recovery
of motor function was limited to the larger muscle groups but
they often enabled the patients to perform most daily activi-
ties. The level of satisfaction was slightly higher in the bilateral
hand-transplanted patients when compared to unilateral
patients. All of the patients developed protective sensation (31
patients analyzed with a minimum of 1-year follow-up) and
90% regained tactile sensibility. The time to development of
distal sensory and motor recovery was correlated to the level
of amputation. It was noted that the more distal the level of
amputation, the faster the recovery of the transplanted hand.
This finding has called into question the level at which to offer
a hand transplant but currently there are no firm recommen-
dations from any of the active groups.
Several of the groups included in the international registry
analysis have also published individual reports. The group
from Poland has recently published follow-up on two patients
who have undergone successful hand transplantation.233 The

635
Future of transplantation in plastic surgery
T-cell-depleting therapies have been effective at promoting
graft acceptance and tolerance in several animal models.251,252
However, clinical translation of these protocols had not
yielded significant progress until the introduction of the anti-
CD52 monoclonal antibody, alemtuzumab (Campath-1H).
CD52 is expressed on most T and B lymphocytes, NK
cells and monocytes, and alemtuzumab rapidly depletes
these cells with varying kinetics of repopulation. The initial
clinical reports by Calne et al.90,91 suggested that the use of
alemtuzumab in combination with low-dose cyclosporine in
kidney transplantation could achieve a state of “prope” toler-
ance (graft acceptance with reduced immunosuppression).
However, the use of alemtuzumab alone or in combination
with deoxyspergualin led to 100% acute rejection.253,254 This
demonstrated that alemtuzumab was not in itself tolerogenic.
Its use as an induction agent has recently been demonstrated
to significantly reduce the episodes of biopsy-proven acute
rejection (14% versus 26%) when compared with thymoglobu-
lin. However, there was no difference in survival, initial length
of stay, and maintenance immunosuppression (including
early steroid elimination).255 Attempts to use T-cell depletion
agents such as alemtuzumab or ATG in the field of CTA have
yielded similar results and highlight the need for additional
strategies to allow for the reduction of immunosuppression.
VCA offers some unique advantages to develop innovative
treatment protocols, such as continuous monitoring and
adequate biopsy sampling of the graft by simple visual
inspection of the skin, allowing for a timely intervention,
treatment, and precise adjustments of immunosuppression on
an individualized basis. In addition, some VCAs may contain
varying amounts of donor bone marrow and a vascularized
bone marrow niche, which could serve as a continuous source
of donor cells, including bone marrow-derived stem cells.
This has been demonstrated in certain experimental animal
models to modulate the host immune response favorably.
Hence, novel cell-based strategies to minimize immunosup-
pression or induce immune tolerance are particularly appeal-
ing in VCA.
The group at Johns Hopkins University introduced a strat-
egy (while at the University of Pittsburgh), that takes advan-
tage of the cellular depletion provided by alemtuzumab,
combining it with a delayed donor bone marrow cell infusion.
This technique had some reported success with living related
kidney transplants; and appears to enable minimization of the
maintenance of immunosuppression after liver, pancreas,
heart and lung transplantation. They performed 8 hand/
forearm transplants in 5 patients under this protocol at the
University of Pittsburgh. The recipients have been maintained
on a single immunosuppressive drug (tacrolimus) at low
levels and continue to have increased motor and sensory
function of their transplanted hands. Despite the combination
of alemtuzumab induction and the donor bone marrow cell
infusion, all of the transplants have experienced at least one
episode of acute rejection that required additional treatment.
However, acute episodes of skin rejection observed with this
protocol were responsive to topical therapy alone in about
50% of cases or short courses of steroids. Both superficial and
deep tissue biopsies as well as high-resolution ultrasound did
not show any evidence of vascular myointimal proliferation
as an indirect sign of chronic rejection. This bone marrow
cell-based immunomodulatory protocol has been proven to
be well tolerated and efficacious and has allowed hand/
questions surround the best use of immunosuppression and
immunosuppressive regimens. It highlights the importance
for future collaborations between centers to address best
practice in the immunosuppression regimen. This review also
reveals the need for continued collaborations between groups
to standardize the way in which functional outcomes are
measured so that case outcomes can be compared more easily.
Facial transplantation
A total of 37 face transplants have been performed (20 partial
and 17 full face) from 2005 to December 2015 (Table 32.4).10
There are some discrepancies between actual transplantations
performed and those reported in peer-reviewed journals, with
some underreporting of the transplants performed. All of the
patients have experienced rejection episodes but the majority
of these have been successfully treated. These transplants
have restored form and function in the majority of the patients.
Post-transplant malignancies have increased in incidence,
and a total of six patients have died. The first face transplant
patient, performed in Lyon, France, recently died secondary
to non-small cell lung cancer likely related to her history
of smoking. She also exhibited donor specific antigen
that may have led to the rejection of her sentinel flap and later
her lower face. The second face transplant patient died sec-
ondary to non-compliance with his medications. The other
deaths were related to recurrent head and neck cancer and
necrotizing infection after attempted combined hand and face
transplant.246–248
Future of transplantation in
plastic surgery
The current strategy for the post-transplant management of
composite tissue allograft is to treat them with well-established
regimens of immunosuppression used in solid-organ trans-
plantation. The majority of VCA transplant patients have been
treated with an induction agent (such as ATG or alemtuzumab)
and then maintained with up to three immunosuppressive
medications (tacrolimus, MMF, and steroids). This has led to
a high level of success in terms of initial graft survival. It has
not prevented episodes of acute or chronic rejection. However,
in order for the field of reconstructive transplantation to
expand its indications beyond the current limited experience,
techniques need to be designed either to significantly reduce
or eliminate the need for chronic immunosuppression. The
future direction of this field is heavily dependent on the
development of innovative approaches to the use of immuno-
suppressive agents and tolerance induction protocols.
Many still regard the use of chronic immunosuppression
to achieve transplantation of limb or a facial allograft difficult
to justify clinically.249 Development of effective regimens to
induce host tolerance without long-term immunosuppres-
sion, therefore, is essential to alter the risk–benefit balance.
Such regimens may involve site-specific immunosuppression
directed at the graft, monoclonal antibodies that block a
particular step in the process of antigen recognition, or expo-
sure to donor antigen with the introduction of hematopoietic
stem cells either before or at the time of transplantation to
establish a state of mixed chimerism.250

636
CHAPTER 32 • Transplantation in plastic surgery
of tolerance for musculoskeletal allografts has been achieved
in experimental swine and rodent models, respectively.265–267
Successful adaptation of this approach could even have
therapeutic potential for congenital conditions. Similar appli-
cation of mixed chimerism protocols could also lead to toler-
ance induction in adults.100,268 Foster et al. demonstrated that
rodent mixed chimeras would accept syngeneic donor limb
allografts.269 Huang et al. have used a minimally toxic protocol
to generate mixed chimeras in the miniature swine with in
vitro donor-specific tolerance while preserving immunocom-
petence to third-party antigens.270,271 Employing a similar
strategy in the same model, Hettiaratchy et al. demonstrated
tolerance to the muscle and bone portions of VCA allografts
across a major MHC barrier.272 In addition, case reports have
shown tolerance to a kidney allograft in patients who received
a bone marrow transplant from the same donor, sometimes
years apart.273–275 However, the combination of most condi-
tioning regimens combined with the infusion of bone marrow
often results in GvHD. The greater the genetic disparity
between the bone marrow recipient and the donor, the more
likely the recipient will develop GvHD.
These findings led Sachs and colleagues to embark on a
clinical trial using this approach to attempt to induce toler-
ance in patients with end-stage renal disease and advanced
multiple myeloma using HLA-identical sibling donors.276 Six
patients received cyclophosphamide, ATG, and thymic irra-
diation as well as cyclosporine (which was tapered off after 2
months) and subsequently followed by donor leukocyte infu-
sions to improve graft-versus-tumor effects.277,278 All patients
demonstrated initial engraftment of the donor marrow but the
donor cell chimerism was lost in all of the patients except two.
These two patients converted to full donor chimerism and
had to be treated for GvHD. The other 4 patients maintained
long-term renal function (up to >9 years) in the absence of
immunosuppression. One of the 4 patients did have a single
forearm transplantation with low-dose tacrolimus mono-
therapy but does not appear to allow for the complete with-
drawal of all immunosuppression. Unfortunately two of the
patients had issues with compliance and have had their uni-
lateral hand transplants removed. There are still three from
the original group, and two more recent transplants have been
performed at Johns Hopkins. Long-term data and follow-up,
however, are still needed to confirm these findings.
The use of a single antibody may not have the ability to
lead to tolerance of donor antigen. Thus the addition of other
monoclonal antibodies, such as CD40 ligand, may be needed
to produce a state of T-cell anergy to these antigens. It has
been observed that full activation of T cells requires both
cell–cell interaction and simultaneous delivery of costimula-
tory signals. A T cell that encounters foreign antigen in the
absence of necessary cytokines fails to activate, which may
lead to a state of tolerance.256 This mechanism is based on the
blockade of CD28/CTLA4–CD80 and the CD40–CD40 ligand
(CD154) pathways.257,258 Several nonhuman primate tolerance
models to evaluate the effect of interrupting these critical
pathways have demonstrated prolonged survival of renal
allografts.259,260 It remains to be seen whether such strategies
could allow limb transplantations to be performed with the
ultimate cessation of immunosuppression.
However, it currently appears that T-cell depletion alone
(with or without bone marrow) or the reliance on other anti-
bodies is unlikely to lead to tolerance of organ allografts.
Regimens that lead to the induction of mixed hematopoietic
chimerism, however, have been shown to lead to tolerance of
organ allografts in multiple preclinical studies.100,261–263 The
strategy involves the use of bone marrow or stem cells to
induce a state of mixed chimerism. Owen observed more than
half a century ago that it is possible to induce tolerance by
exposing the donor’s bone marrow to the recipient’s immune
system before its maturity.264 Such fetal or neonatal induction
Table 32.4  Face transplants performed worldwide
Center (country)
Partial face patients
Total face patients
Total face transplants
Mortalities
Amiens (France)
3
3
1
Xi’an (China)
1
1
1
Paris (France)
6
1
7
2
Brigham and Women’s
Hospital (USA)
3
4
7
Valencia (Spain)
1
1
1
Seville (Spain)
1
1
Barcelona (Spain)
2
2
Ghent (Belgium)
1
1
Antalya (Turkey)
2
3
5
1
Ankara (Turkey)
1
1
2
University of Maryland (USA)
1
1
Gliwice (Poland)
2
2
Cleveland Clinic (USA)
2
2
St. Petersburg (Russia)
1
1
New York University (USA)
1
1
Total
20
17
37
6

637
Future of transplantation in plastic surgery
transiently achieved in all patients but donor cells could not
be detected after day 21 and GvHD did not develop.
One patient lost his kidney graft as a result of an early and
irreversible antibody-mediated rejection. In the other 4
patients, immunosuppression was successfully withdrawn
during the first year post-transplant and normal renal func-
tion has been sustained for more than 3–6 years to date. The
mechanisms underlying this operational tolerance are not
fully elucidated. This model is also designed for living related
transplants and in its current form would not be possible for
VCA transplants.
rejection episode that was controlled by the transient use of
immunosuppression.
The group recently modified its protocol to address the
induction of tolerance in recipient kidneys from HLA-mis-
matched living donors. To reduce the risk of GvHD they now
use an anti-CD2 monoclonal antibody (siplizumab or MEDI-
507) for its T-cell depletion rather than ATG. Five patients
received cyclophosphamide, MEDI-507, thymic irradiation,
and cyclosporine.279 Occurrences of humoral rejection and
engraftment syndrome led to the addition of rituximab and
corticosteroids for the last 2 patients.280 Mixed chimerism was
1. Harrison JH, Merrill JP, Murray JE. Renal homotransplantation in
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detailed case report, a background discussion of considerations in renal
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5. Petruzzo P, Lanzetta M, Dubernard JM, et al. The International
Registry on Hand and Composite Tissue Transplantation.
Transplantation. 2010;90:1590–1594. Follow-up on all cases recorded in
the International Registry on Hand and Composite Tissue
Transplantation through July 2010 is included in this publication.
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transplantation for a severely disfigured patient in the USA.
Lancet. 2009;374:203–209. A case of near-total (80%) human facial
transplantation is reported with dramatic functional improvements and
free from major complications. The authors posit that facial
transplantation should be considered as an early reconstructive option for
patients with severely disfiguring facial injuries.
7. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the lower
and middle parts of the face by composite tissue
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neurofibroma: a 1-year follow-up study. Lancet. 2008;372:
639–645.
8. Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months
after the first human partial face transplantation. N Engl J Med.
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transplant in 2005. This report reviews the procedure’s outcomes from
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242. Carroll D. A quantitative test of upper extremity function. J Chronic
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243. Hudak PL, Amadio PC, Bombardier C. Development of an upper
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246. Kanitakis J, Petruzzo P, Gazarian A, et al. Capillary thrombosis in
the skin: a pathologic hallmark of severe/chronic rejection of
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247. Kanitakis J, Petruzzo P, Badet L, et al. Chronic rejection in
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and face recipients): an update. Transplantation. 2016;100:
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248. Petruzzo P, Kanitakis J, Testelin S, et al. Clinicopathological
findings of chronic rejection in a face grafted patient.
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249. Mathes DW, Randolph MA, Lee WP. Strategies for tolerance
induction to composite tissue allografts. Microsurgery.
2000;20:448–452.
250. Sykes M. Immune tolerance: mechanisms and application in
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251. Knechtle SJ, Vargo D, Fechner J, et al. FN18-CRM9 immunotoxin
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252. Thomas JM, Neville DM, Contreras JL, et al. Preclinical studies of
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253. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal
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254. Kirk AD, Mannon RB, Kleiner DE, et al. Results from a human
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255. Farney AC, Doares W, Rogers J, et al. A randomized trial of
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costimulation mediated by reorganization of membrane
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262. Kawai T, Cosimi AB, Colvin RB, et al. Mixed allogeneic chimerism
and renal allograft tolerance in cynomolgus monkeys.
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266. Mathes DW, Solari MG, Randolph MA, et al. Long-term
acceptance of renal allografts following prenatal inoculation with
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to transplantation tolerance. Immunol Today. 1988;9:23–27.
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33 
Technology innovation in plastic surgery:  
A practical guide for the surgeon innovator
Leila Jazayeri and Geoffrey C. Gurtner
SYNOPSIS
■ Plastic surgeons have historically been distinguished by their ability to
innovate and should continue to maintain this competitive advantage.
■ This chapter will familiarize the surgeon innovator with a systematic
approach to innovation. This process includes idea formation,
valuation, funding, intellectual property, institutional technology transfer,
the FDA regulatory process, and conflicts of interest.
■ Negative pressure wound therapy, acellular dermal matrix, and
noninvasive body contouring are used to discuss the impact of
innovation within plastic and reconstructive surgery.
Introduction
Innovation drives the advancement of medicine. Recent
medical innovations, from evidence-based medicine and
information technology to robotic and laparoscopic surgery,
have revolutionized the practice of medicine. In the surgical
arena, innovation has led to increasingly effective and less
invasive therapies resulting in better patient care.
What separates invention from innovation? Invention is
the formulation of new ideas for products or processes, while
innovation creates the application of new inventions. In busi-
ness, invention uses cash to create a product and innovation
takes a product and creates cash. In medicine, invention is an
attempt to create a solution to a clinical problem and innova-
tion drives the solution to the bedside – analogous to the
process by which translational research applies basic science
to clinical problems.1
Plastic surgeons, by trade, are innovators. We devise inno-
vative solutions to difficult problems. Our competitive
advantage lies in innovation. Unlike the neurosurgeon or
cardiologist, we do not lay claim to any one part of the
body.2 In the hospital we are called upon for our creative
solutions to the neurosurgeon’s need for calvarial reconstruc-
tion, the cardiac surgeon’s need for chest wall reconstruction,
and the orthopedic surgeon’s need for hardware coverage.
Our innovative spirit transcends beyond innovative surgical
methods and encompasses innovation of novel technologies
as well. Historically, microsurgery, distraction osteogenesis,
tissue expansion, endoscopic plastic surgery, liposuction and
laser technology have all served as platforms for expanding
the scope of our practice, as well as expanding the scope of
what we can offer our patients.3
The expansive breadth of plastic surgery exposes our field
to multiple competing subspecialists. Dermatologists, otolar-
yngologists, ophthalmologists, obstetricians and internists are
increasingly involved in aesthetic surgery. Similarly, general
surgeons are competing for abdominal wall reconstruction,
breast reconstruction, and wound healing. Otolaryngologists
compete for head and neck reconstruction. Orthopedic sur-
geons compete for hand cases. Each of these fields involves
important new innovations, and subsequently opportunities
for patient care, research, and revenue. Aesthetic surgery is
riddled with novel technologies including skin resurfacing
techniques, noninvasive body contouring, injectables, and
laser therapy. The attractive revenue stream in this cash-based
field is obvious and draws in more and more competition.
Similarly, abdominal wall reconstruction has been revolution-
ized by the introduction of new biomaterials. Breast recon-
struction is changing with the introduction of new breast
implants, fat grafting and dermal substitutes. The field of
wound healing has dramatically changed with negative pres-
sure wound therapy. Head and neck reconstruction has seen
the introduction of bioabsorbable plates, screws and alloplas-
tic bone substitutes, while PyroCarbon arthroplasty and
artificial nerve conduits continue to expand the offerings
of hand surgery. Innovation is the sustainable competitive
advantage for plastic surgeons in this competitive clinical
reality.
Today, however, the arena of medical innovation is far
more complex than it was 50 years ago. There is more scrutiny
from the US Food and Drug Administration, an exponential
growth in the number of patents filed and more complexity
in regulatory pathways for new medical products. In the
setting of a healthcare and economic crisis, it is harder to

639
Determining the value
technician. He met much criticism from his mentors but went
on to patent the balloon catheter, built the device in his garage,
and worked tirelessly to have the catheter adopted by vascular
surgeons. The Fogarty catheter has since revolutionized vas-
cular surgery and led to a platform for innovations in mini-
mally invasive techniques.
Whether accidental or systematically created, the idea
behind an innovation can lead to the development of two
broad categories of innovations: a novel method or a novel
device. Because the majority of the chapter discusses medical
devices, we will briefly discuss the innovation of novel
methods. Delos Cosgrove describes his idea for a novel surgi-
cal method: “Several years ago, in preparation to perform
aortic valve replacement, I found the ascending aorta entirely
calcified and both femoral arteries occluded. Recognizing the
danger of cannulating either one of these vessels, I raised
the patient’s arm to expose the axillary artery, which I used
as the cannulation site. The aortic valve replacement was
successfully performed.”6 Bruce Lytle expanded this idea and
refined the process of cannulating the subclavian artery for
this problem. Substantial changes to a surgical intervention
are reviewed by the Institutional Review Board (IRB), funded
through academic sources, and described in new academic
publications and presentations. The surgical community
generally shares new methods without recovering royalties
for the benefit of patients, even though novel surgical methods
can be patented if desired.7
Determining the value
Value is the subjective relationship between the perceived
benefit and perceived cost of a product or service.
Value
percieved benefit
percieved cost
=
As physicians, we are constantly assigning value to our thera-
pies as a means of deciding how to provide medical care. We
define the value of a given therapeutic intervention as the
potential benefit to the patient in relation to the potential risk.
Based on the risk–benefit ratio, we decide to proceed with or
abandon a given therapy. Similarly, as surgeons we define the
value of a surgical innovation as the potential benefit to the
patient in relation to the potential risk. Based on the risk–
benefit ratio, we decide to adopt or not adopt an innovation.
In today’s healthcare arena, before any novel surgical device
is even available for use at the patient’s bedside, its com-
mercial value must be demonstrated. The commercial return
on a device must outweigh its development risks in order to
have a realistic chance of having the device available for
patient use. To understand the value of an innovation, it is
important to understand the perceived benefit the innovation
has on (1) patient care, (2) technology, and (3) commercial
impact (Box 33.1). We will review some of the terms used to
describe an innovation’s perceived benefit in these arenas.
The impact an innovation has on patient care can be
described as revolutionary or incremental. A revolutionary
innovation has a significant impact on patient care where
an incremental innovation has a smaller effect. Consider
the revolutionary impact of the endograft for repair of
abdominal aortic aneurysms (AAA). The technique of using
justify increased development expenses with increased com-
petition for limited investment funds. When the surgeon is
asked to innovate, he/she also faces a plethora of challenges
unique to the surgeon innovator including conflict of interest
concerns and navigating within the confines of the intellectual
property claims of universities.4 The challenges faced by
today’s surgeon innovator are captured well by Machiavelli’s
The Prince: “There’s nothing more difficult to plan, nor more
dubious of success, nor more dangerous to manage than the
creation of a new order of things. Whenever his enemies have
the ability to attack the innovator, they will do so with a
passion of partisans while others defend him sluggishly so
that the innovator and his party are likely to be vulnerable.”
The enterprise of surgical innovation may receive little support
and face many barriers, however it can create new technolo-
gies that may revolutionize a field and impact millions of
patients. To overcome today’s barriers to surgical innovation,
we must create and use a systematic approach to translate
ideas based on a human problem into a product that can
change clinical practice.5 This chapter sets out to discuss a
systematic approach to surgical innovation and gives a few
examples of new technologies in our field.
The idea
Mark Twain said, “The name of the greatest of all inventors
is accident.” In 1957, Mason Sones accidently injected the
right coronary artery with dye, he immediately recognized
the problem and pulled the catheter out while the injection of
dye continued. He later said, “That day I realized that I had
discovered something very important.” He then went on to
refine the technique that led to coronary angiography. On the
other hand, Plato’s frequently cited proverb, “necessity is the
mother of invention” hints that innovation certainly does not
need to rely on an accidental discovery.
Today, there are calculated and systematic innovation para-
digms that start with the identification of a clinical problem.
The problem should be an unmet clinical need. The scientific
knowledge in the arena and the limitations of the current
solutions should then be explored. The clinical problem can
be taken to the laboratory or into multidisciplinary think
boxes where a solution is systematically developed, with the
hope of translating it back to the operating room. Robert Frost
thought that ideas are feats of association, “Having what is in
front of you brings up something in your mind that you
almost didn’t know you knew.” This paradigm of discovery
may describe why the majority of surgical devices are rooted
in the ideas of observant surgeons. The timeless story of Dr.
Thomas Fogarty’s development of the Fogarty catheter started
with a defined clinical problem and was assisted with “feats
of association.” Fogarty was a scrub technician and witnessed
acute limb loss as a result of surgery to remove blood clots.
As a medical student of the University of Cincinnati, he
started to work on a solution to the clinical problem he had
identified years previously. In his garage, he developed a
balloon on the tip of a catheter that could be inserted through
a small access incision and passed through the artery beyond
the blockage. Once past the blockage, the balloon could
be inflated and the clot dragged out of the artery. His ability
to invent and prototype this novel device was perhaps facili-
tated by his prior association with surgical tools as a scrub

640
CHAPTER 33 • Technology innovation in plastic surgery: A practical guide for the surgeon innovator
“industry leader” can be applied to the corporation that
produces the leading technology, or more broadly the subspe-
cialty that uses the technology. For example, when percutane-
ous transluminal balloon angioplasty was introduced, its
safety profile was not well understood and it was inferior to
open coronary artery bypass. Over time, it proved to be a
disruptive technology that shifted the market share of patients
away from cardiothoracic surgeons (the incumbent industry
leaders) to interventional cardiologists. The coronary stent,
on the other hand, was a sustaining technology. A sustaining
technology change is an improvement, usually made by the
current industry leader, to maintain growth in the market. The
technology can still be enabling (leading to further technology
changes) or revolutionary (leading to significant improve-
ments in patient care) but by definition it is not disruptive to
market forces. In this case, the coronary stent led to further
technologic advancement and improved patient outcomes but
did not supersede industrial or clinical leaders. The interven-
tional cardiologist used this technology to maintain their
growth in the market.1
Generally, the larger the perceived benefit of an innovation,
the larger the potential for financial return; however, there
a transfemoral intraluminal graft for repair of AAA was first
published by Balko and associates in 1986, the first published
human experience was by Parodi in 1991, and the first device
manufactured was designed by Harrison M. Lazarus and
developed by Endovascular Technologies Company.8–10 In
September 1999, two devices were granted FDA approval for
marketing. Now endovascular repair of AAA offers shorter
hospital stays, decreased operative mortality and morbidity
and an undisputed advantage to patients with multiple or
significant comorbidities. On the other hand, consider the
reiterations of multiple laparoscopic dissectors. These instru-
ments have been developed in the attempt to improve lapa-
roscopic dissection, but none with a significant impact on
patient outcomes or care.
The impact an innovation has on technology can be defined
as enabling or refining. An enabling technology is an innovation
that serves as a platform for further developments within a
field. In 1976, the Fischers introduced the modern era of
liposuction, which is now one of the most commonly per-
formed cosmetic surgery procedures.11 This innovation has
served as a platform for many further developments includ-
ing ultrasound and power-assisted liposuction. Both ultra-
sound and power-assisted liposuction represent refining
technologies. A refining technology is an innovation that mar-
ginally improves upon available technology and does not lead
to a significant technology change.
Finally, to help describe the commercial impact of an innova-
tion, the market-based terms “disruptive technology” and
“sustaining technology” are used (Fig. 33.1). A disruptive
technology is an innovation that supersedes industry leaders
and takes over their market share. When disruptive technolo-
gies are introduced they are often inferior to the existing
leading device and ignored by the incumbent industry leader.
In surgery, the device’s inferiority is usually secondary to the
device’s learning curve, lack of safety information, and infe-
rior technology. However, as clinicians learn to use the device,
as its safety profile expands and as the technology improves,
its market share surpasses that of its leading competitor. The
BOX 33.1  Determining the value of an innovation
Impact on patient care
• Revolutionary innovation: significant impact on patient care,
e.g. endovascular repair of AAA
• Incremental innovation: small effect on patient care, e.g.,
reiteration of laparoscopic dissector
Impact on technology
• Enabling innovation: serves as a platform for further
developments within a field, e.g., liposuction
• Refining innovation: marginally improves upon available
technology, does not lead to significant technology change,
e.g., ultrasound and power-assisted liposuction
Impact on market share
• Disruptive innovation: supersedes industry leaders and takes
over their market share, e.g., percutaneous transluminal
angioplasty for interventional cardiology
• Sustaining technology: an improvement, usually by an industry
lead, to maintain growth in the market, e.g., cardiac stent for
interventional cardiology
Fig. 33.1  Disruptive versus sustaining technology change.
Industry leader
New competitor
Industry leader
Time
Market share
Disruptive technology
Time
Market share
Sustaining technology

641
Funding
2009 were estimated at $17.6 billion from 259 480 active inves-
tors, with a total of 57 225 entrepreneurial ventures receiving
angel funding. Healthcare services and medical devices and
equipment accounted for 17% of the investments second only
to software, which accounted for 19%.12 By 2013 angel invest-
ments had increased to $24.8 billion with over 298 000 inves-
tors compared to $29.6 billion from venture capital.13 Small
business technology transfer grants (STTR) reserve a specific
percentage of federal R&D funding for partnerships between
small businesses and nonprofit research institutions. The idea
is to combine the innovative ideas that tend to come out of
small businesses or academic centers that lack the means to
support serious R&D, with the ability of non-profit research
laboratories to develop high-tech innovations. The goal of
these partnerships is to transfer the technologies from the
laboratory to the marketplace, with small businesses profiting
from the commercialization and thus stimulating the US
economy. Each year, the Department of Defense, Department
of Energy, Department of Health and Human Services,
National Aeronautics and Space Administration, and the
National Science Foundation are required by STTR to reserve
a portion of the R&D funds towards these partnerships.
Larger investments can come from venture or corporate
funding. Venture capital funds pool together investments
from institutional investors and high net worth individuals.
These investors become limited third party investors in the
venture fund. The fund then invests in novel technologies that
have the potential to generate high commercial returns at the
expense of risks too high for the standard capital markets. In
exchange for the high risk, venture capital funds buy a sig-
nificant amount of control and ownership of the company. To
ensure realization of the high risk investments, firms look for
companies with an innovative technology with the potential
for rapid growth with a well-developed business model,
impressive management team, and markets valued at greater
than $500 million.
Venture capital is offered in stages, the funding stages
parallel the growth of the company. As the new enterprise
moves from concept, to company, to product, and finally
acquisition, buyout or IPO it gains value and sheds risk.
Venture capitalists require a detailed analysis of the develop-
ment pathway with a focus on reducing risk and building
value at critical growth milestones. Examples of critical mile-
stones are securing IP, building a working prototype, success-
ful animal testing, FDA approval and first-in-man use.
Paralleling each of these growth milestones are funding
benchmarks. The first funding benchmark is the seed stage;
as discussed above, this can come from friends and family or
angel investors. Many venture capital funds may not invest
at the seed stage because the risks are very high and the
concept has not been fully realized at this point. The second
benchmark is known as start-up stage where the venture is
ready to launch; these funds are required for company devel-
opment, marketing, and product development. The third
benchmark, which can be further divided into several rounds,
is the expansion stage. Funds here are used for manufactur-
ing, sales, and getting a company to a stage where it starts to
turn profits. Often the final financing round is the mezzanine
or bridge round which is prior to the final acquisition, buyout,
or IPO. In this stage, short-term debt is usually used to support
growth opportunities while preparing for an acquisition, a
buyout or an IPO.
also tends to be more risk involved in all stages of its develop-
ment. With a revolutionary innovation, there is significant
risk in developing the unproven technology, a riskier FDA
approval pathway usually requiring pre-market approval,
and more resources needed to create a large and experienced
development team that can handle the challenges involved in
developing a revolutionary technology. A revolutionary
innovation, such as the endograft for AAA repair, will also
have a large patient impact and large potential market that
will justify the increased resources and risk required to
develop the device. An incremental innovation, such as the
“bullet” endoscopic dissector, has a smaller patient impact
and ultimately less potential revenue. To justify its value,
there must be less risk and resources involved in its develop-
ment. Indeed there is less risk in the technologic feasibility
of incremental technologies because they generally rely on
proven technologies, the FDA regulatory pathway generally
falls in a “510(k) pathway”, with faster approval based on
predicate devices, and the development team can be a small
group of focused individuals. It is important to understand
what general category a new innovation falls in so that the
risks and subsequently expected benefits can generally be
understood.
Funding
An innovative idea develops from concept, to product, to
patient use in a stepwise manner. As each milestone is met,
the innovation builds value and reduces risk (Fig. 33.2).
Funding throughout this process is acquired based on pro-
gress towards building value. The initial smaller investment
used to prove the innovative concept is termed seed money.
This smaller investment is generally $50 000–$500 000 and can
come from a variety of sources: friends and family, angel
investors, device company grants, small business innovation
research (SBIR) and technology transfer (STTR) grants. Angel
investments come from affluent individuals or a group of
individuals, often with industry expertise, usually in exchange
for ownership equity in the company. Angel investments in
Fig. 33.2  Stages of funding.
Concept
Company
Product development/
clinical trials
Sales/profits
Liquidity
Seed stage
Start-up
Expansion
Mezzanine
Value
Risk

642
CHAPTER 33 • Technology innovation in plastic surgery: A practical guide for the surgeon innovator
connected, to make and use the same, and shall set forth the
best mode contemplated by the inventor of carrying out his
invention”. Finally, the claims section is used to describe the
scope of protection the applicant is requesting. This section is
critical and forms the bases for litigation and prosecuting
infringement. Here, technical language should be used to
really define the embodiments of your innovation that dif-
ferentiate it from inventions that came before. In patent lan-
guage, prior inventions are referred to as prior art. The claims
section really defines the invention. Most patents contain
about 10–20 claims, though there are some patents with only
one claim and others with hundreds of claims. There are two
types of claims: independent claims and dependent claims.
Independent claims stand alone. Dependent claims, on the
other hand, refer to another claim on which it depends, and
it has to be read in conjunction with that claim to understand
the scope of the claim.
A full utility patent application includes the figures, written
specifications, and claims as detailed above. Legal counsel,
specializing in intellectual property, is advisable at this stage,
as the surgeon inventor usually does not have the expertise
to ensure that the utility patent meets both the inventor’s and
the USPTO’s expectations. Since June 8, 1995, the USPTO has
offered inventors the option of filing a provisional patent appli-
cation to provide a lower cost ($110–220) first patent filing in
the United States. A provisional patent protects an invention
in its early stages. This document describes the inventions
with relevant drawings, without making any claims. Once it
is submitted, the USPTO files the information but does not
review it until a full utility patent application is ready for
review. The provisional patent is valid for a year while the
inventor perfects the invention and the utility patent applica-
tion. Patentability is then evaluated as though filed on the
earlier provisional application filing date, however the 20-year
patent term would be measured from the later nonprovisional
application filing date.
While a provisional patent offers documented protection
of an invention in its early stages, patents in the United
States are theoretically issued to the “first-to-invent” as
opposed to the “first-to-file” approach taken by other coun-
tries. It is thus very important to have adequate proof of the
date of inventions through a laboratory notebook that is
dated, signed, and witnessed on a regular basis. This docu-
mentation of an invention can ultimately alter a patent’s
recipient. A surgeon inventor should thus carefully docu-
ment all inventions, once an invention is deemed novel,
unobvious, and useful; perform an initial patent search and
then file a provisional patent. Beyond the provisional patent,
additional counsel should be obtained. At an academic insti-
tution this counsel can be obtained through the technology
licensing office.
Institutional technology transfer
In 1980, the Bayh–Dole Act enabled small businesses as well
as public and nonprofit organizations, including universities,
to retain intellectual property developed during the pursuit
of federally sponsored research and development. Since then,
there has been an explosion of new relationships between
universities, industry, and the federal government. Research
universities have not only developed increasingly close ties to
The first round of external funds is generally called “Series
A” and the second round “Series B”. The investment vehicle
is generally “Series A Preferred Stock” or “Series B Preferred”.
This is preferred equity share in the company, meaning in
exchange for their investment, the venture capital (VC) group
will have first right to dividends in the case of success and
liquidated assets in the case of failure. The equity share in
each round is determined by the value of the company at that
stage or the “pre-money valuation” in relation to the invest-
ment of the VC firm.
Intellectual property
The US Patent and Trademark Office (USPTO) issues several
different types of patent documents covering different types
of subject matter. Medical devices are most often protected by
utility patents. Approximately 90% of the patent documents
issued by the USPTO in recent years have been utility patents.
Utility patents protect any new invention or functional
improvements on existing inventions. This can be to a product,
machine, a process, a method of making things, or composi-
tion of matter. A patent does not grant the right to use or sell
an invention, rather it grants the right to exclude others from
making, using, selling, offering for sale, or importing the
invention in the United States for up to 20 years from the date
of patent application filling. Thus, if an inventor takes a pat-
ented laparoscopic grasper and adds a design to make it more
ergonomic, and then obtains a new patent on that improve-
ment, he or she can exclude others from using their improve-
ment. However, the new inventor needs the permission of the
original laparoscopic grasper to manufacture theirs.
To be considered for patent, an invention must be novel,
unobvious, and useful. To be novel, the invention cannot have
been known or used by others or even described in a printed
publication. Specifically, a US patent cannot be obtained after
1 year from the time an invention has been revealed through
public use or publication. In many countries, the 1 year grace
period is not granted. Thus, inventors in the academic envi-
ronment should obtain intellectual property prior to publish-
ing their work and surgeon inventors should likewise obtain
intellectual property prior to public use. The invention must
also be unobvious to those involved in the relevant field.
Finally, it must be useful, in the case of a surgeon innovator,
it must meet a patient or surgeon need.
To make sure an invention or idea is novel, the surgeon
innovator can search the literature and the USPTO database.
One can begin by using keyword searches to find a similar
device on any publically available search engines.14,15 Once the
closest device or invention is found, the existing patent should
be intimately explored to understand which aspects of the
innovation are protected and which are not.
There are three main parts of a patent: the figures, the
written specifications, and the claims. The patent figures or
drawings are required of almost all utility patents. The draw-
ings must show every feature of the invention specified in the
claims, and are required by the USPTO rules to be in a par-
ticular form. The written specifications are a written descrip-
tion of the invention, how to make it, and how to use it. The
USPTO states that the specifications should be, “in such full,
clear, concise, and exact terms as to enable any person skilled
in the art to which it pertains, or with which it is most nearly

643
FDA regulatory approval process
medical devices available in a timely manner. To determine
the safety and efficacy of a medical device, the CDRH has
developed three main approval pathways: exemption, 510(k)
pre-market notification, and pre-market approval application
(PMA) (Table 33.2). The approval pathway is determined by
the degree of risk associated with the device and the extent to
which it poses new safety and efficacy concerns. Devices are
also classified according to their perceived risk and the extent
of control needed to ensure safety and effectiveness with a
3-tiered system: class I, class II, or class III. Regulatory control
increases from class I to class III.
In general, device class loosely correlates with corre­
sponding FDA approval pathways. Most class I devices are
exempt from pre-market notification (PMN) or pre-market
approval (PMA); most class II devices require pre-market
notification 510(k); and most class III devices require pre-
market approval. Class I devices are considered the lowest
risk devices. They are subject to general controls. General
controls are published standards regarding labeling, manu-
facturing, pre-market surveillance, and reporting. Devices are
placed in this class when general controls alone are sufficient
to assure safety and efficacy. Examples of class I devices are
hand-held surgical instruments. A total of 47% of medical
devices fall under this category and 95% of class I devices are
exempt from pre-market notification (PMN) and 510(k) FDA
approval pathways.20
Class II devices are higher-risk devices. General controls
alone are insufficient to provide assurance of safety and
effectiveness. There is, however, enough information avail-
able to ensure safety and efficacy with special controls includ-
ing performance standards, design controls, and post-market
surveillance. Most medical devices are considered class II
devices. Examples of class II devices include: powered wheel-
chairs, surgical drapes, surgical needles and suture material,
and some pregnancy-test kits. A total of 43% of medical
devices fall under this category. Approval of most class II
devices requires pre-market notification 510(k). There are
about 60 generic class II devices that are exempt from pre-
market notification, as long as they meet the requirements of
General Controls and Special Controls.
Class I and II devices that require more than General
and Special Controls require pre-market review by the FDA
with PMN or 510(k). Under 510(k), a manufacturer must
industry, but through licensing and other forms of technology
transfer, universities have become an important force in the
development of technology which has ultimately contributed
significantly to local regional economic development.16–19 In
the last two decades, institutional prestige for research uni-
versities has been increasingly defined in terms of commercial
success, in addition to academic sciences.18
Most universities have created technology-licensing offices
(TLO) to manage their patent portfolios. Surgeon innovators
should become familiar with the intellectual property (IP)
policies of their specific institution. Most universities have an
employee contract that claims IP on any invention created
with university resources. Under the Bayh–Dole Act, however,
universities are also required to share a portion of new tech-
nology revenues with the inventor. The surgeon innovator
thus generally begins the process of invention with disclosure
of the invention to the TLO. The TLO then evaluates the
technology and almost invariably chooses to retain the intel-
lectual property. At this point, depending on the competencies
and culture of the TLO, an active or passive role is taken to
market a technology to industry and potential developers with
the initial goal of understanding the invention’s true value.
Once the technology and its financial potential are understood,
again depending on the culture of the TLO, various steps are
taken to develop and license the technology. A fair opportunity
to license the technology is generally given to the inventor.
There is a huge spectrum of licensing agreements and stipula-
tions that can or cannot be included in a licensing agreement.
Some general licensing terms are outlined in Table 33.1.
FDA regulatory approval process
In the United States, medical devices are regulated by the
Center for Devices and Radiological Health (CDRH), a branch
of the FDA. The CDRH is responsible for promoting and
protecting the public health by making safe and effective
Table 33.1  Basic licensing terms
Issue fee
The fee paid to the licensing body for
issuance of the license
Exclusivity
A stipulation guaranteeing that no other
group may license the technology for the
term of the license
Term
The length of a license
Field of use
Granted use of the patent in specific fields,
i.e., medical, industrial, educational
Licensed territory
The specific region granted to the licensee
Annual royalty
payment
The annual fee for use of the license
Equity
Equity in the licensee company can be
granted as part of the payment for a
license
Earned royalty
A percentage of the revenues from products
that rely on the licensed patent, paid to
the licensing body
Sublicensing fee
The fee paid to the licensing body, if the
licensee sublicenses
Table 33.2  Approval pathways
Device
classification
FDA regulatory approval
process
Examples
Class I
Exemption: subject to
general controls
Hand-held
surgical
instruments
Class II
510(k) pre-market
notification: demonstrates
equivalency to class I or
class II devices with
existing 510(k) approval
Suture materials
Class III
Pre-market approval (PMA):
extensive data with
preclinical studies and
human clinical trials
Breast implants

644
CHAPTER 33 • Technology innovation in plastic surgery: A practical guide for the surgeon innovator
innovator serves to benefit from the rewards of both improved
patient care and financial gains as the inventor and possible
developer of a given innovation. However, to help bring an
invention to the bedside, the clinical inventor often becomes
integrally involved in designing and developing the innova-
tion, performing the majority of early animal studies, and
eventually taking a leadership role and holding an equity
position in the company developing the device. These conflicts
of interest must be addressed to ensure patient safety.
There is no one comprehensive regulatory process to
address all the conflicts of interest present in the process of
surgical innovation. However, there are some processes
that help assure third party checks and balances in human
trials. Studies required for PMA approval are typically large
multicenter randomized trials. The study’s sponsor typically
must utilize a contract research organization (CRO), core
laboratories, a data safety monitoring board (DSMB), and an
executive committee, to help resolve potential conflicts of
interest. The CRO helps recruit, qualify, and audit sites. Core
laboratories evaluate primary data in a blinded manner. The
DSMB is composed of a group of senior clinical investigators
and statisticians with no other involvement in the study.
They review the data at specified intervals with a mandate
to stop or modify the study if harm to study participants,
including an obvious benefit in one arm of the study,
becomes evident. Ultimately, it is incumbent on the surgeon
innovator to advance the technology they feel may benefit
their patients. To do so, he/she should try to separate them-
selves, as much as feasible, from activities where financial
gain will bias objective analysis. To help identify and
avoid conflicts of interest, the surgeon innovator should also
provide colleagues and patients with full disclosure of
industry relationships.
Innovations in plastic surgery
Innovation in plastic surgery continues to advance our field.
There is a large list of recent innovations that spans every field
within plastic surgery. The impact of the various new tech-
nologies is as diverse as the technologies themselves. Negative
pressure wound therapy (NPWT) was a revolutionary innova-
tion in its impact in wound care and has proven to be a disrup-
tive technology in its commercial impact. Acellular dermal
matrix (ACM) is being used in more and more applications
within plastic surgery and may become a disruptive technology
that replaces prior synthetic or living tissue substitutes.
Finally, liposuction was an enabling technology that served
as a platform for further refining technologies, including nonin-
vasive body sculpting. This small sampling of recent innova-
tions is discussed below and we briefly touch on the spectrum
of their impact on patient care, the market, and further
innovation.
Negative pressure wound therapy
In the late 1980s, Drs. Louis Argenta, MD and Michael Moryk-
was, PhD, both professors of plastic surgery at the University
of Wake Forest, developed an innovative approach to the
treatment of acute and chronic wounds through the use of
sub-atmospheric pressure known today as negative pressure
wound therapy (NPWT). In 1993, a partnership between KCI
demonstrate that a medical device is substantially equivalent
in intended use, technology, safety and efficacy to: (1) a class
I or II device with existing 510(k) approval or (2) a device
marketed prior to the Medical Device Amendments of 1976,
giving it “grandfather marketing” status. One can search the
FDA’s 510(k) database for devices already on the market or
with grandfather marketing status.21 Once a PMN is submit-
ted, the FDA has 90 days to respond. If the FDA agrees that
the device is “substantially equivalent”, the manufacturer can
market the device. The FDA, on the other hand, can require
further data or determine the device is not substantially
equivalent and re-classify the device as a class III device.
Class III devices pose the highest potential risk. These
devices usually sustain or support life, are implanted, or
present significant risk of illness or injury. Furthermore, they
have a new intended use or technology that is not equivalent
to a prior device. Given the potential safety concerns of class
III devices, general and special controls alone will not provide
enough assurance of safety and effectiveness. Examples
include implantable pacemakers and breast implants. A total
of 10% of medical devices fall under this category and these
devices will usually require pre-market approval (PMA) from
the FDA before they can be legally marketed. The PMA appli-
cation is significantly more involved than the 510(k). Pre-
market approval requires extensive data with preclinical
studies, human clinical trials, and a full description of the
device, including the details of manufacturing and labeling.
Once a PMA is submitted, the FDA has 180 days to perform
a detailed review. The FDA can grant the PMA, require more
data, deny the claim, or accept with the requirement of post-
market surveillance. Any substantial change to a PMN or
PMA device requires new clearance.
Clinical testing of an unapproved device that poses a sig-
nificant risk, or approved devices used for a purpose distinct
from its approved indication, requires FDA approval in the
form of an Investigational Device Exemption (IDE). The IDE
application includes information of the device and the pro-
posed study protocol.22 Both IRBs and the FDA can make the
determination of whether a device will require an IDE. If an
IRB determines that the device’s risk is not significant, FDA
notification is not required and the IRB will oversee the trials.
If the request for determination is initially submitted to the
FDA, the result is binding.22 The applications and approval
leading to first clinical use are important, because first clinical
use is a key milestone for a new device company. In many
cases, if a company fails to reach this milestone within a
reasonable amount of time, its funding and viability will be
threatened. FDA approval to initiate clinical studies in the
United States is estimated to take 3–6 months, with review by
IRBs adding an additional 3–6 months. Because of this time
delay, many companies choose to perform their initial clinical
testing outside the United States. When initial clinical testing
is performed within the United States, only about one quarter
of the trials are performed at academic institutions, largely
attributed to bureaucracy associated with IRBs and contract
negotiations at large academic institutions.23
Conflict of interest
There is an obvious conflict of interest when a surgeon
also becomes an innovator of surgical devices. The surgeon

645
Innovations in plastic surgery
to wound closure, length of hospitalization, complication
rates, and costs.28–35
There is a lack of high level or consistent evidence, however,
to support its superiority when compared with traditional
moist saline dressings in non-diabetic wounds. In these set-
tings, the more clear advantage was that NPWT met additional
surgeon-user needs including decreased number of dressing
changes and ease of use. In the traumatic setting, there are
observational studies that show its efficacy is comparable, but
not superior, to standard dressing changes,36 however the
frequently cited advantages, in the trauma population, are:
ease of application, decreased number of dressing changes,
and reduction in the complexity of subsequent reconstructive
surgery.37,38 In the treatment of pressure ulcers, no statistically
significant differences have been shown in wound surface
area, however the cited advantages have been improved
patient comfort and less labor intensity.39,40
High-level evidence showing the superiority of NPWT
compared with traditional moist saline dressings is still
lacking, however it is clear that NPWT meets very specific
needs of the surgeon or end user. NPWT is easy to use;
it decreases the number of dressing changes for both the
patient and the medical caregiver and ultimately prepares the
wound for surgical closure by tertiary intention. By under-
standing and meeting the needs of the surgical community,
the plastic surgeon and engineer that developed NPWT
changed the armamentarium of the general surgeon’s
approach to the open abdomen, the cardiothoracic surgeon’s
approach to post-sternotomy mediastinitis, the vascular sur-
geon’s approach to groin wounds and, ultimately, the plastic
surgeon’s approach to all of these wounds as well as graft and
flap reconstruction. The clinical adoption, despite lack of high
level and consistent data, makes it a revolutionary technology
that translates into a commercially disruptive technology (see
Fig. 33.3).
Acellular dermal matrix
In recent years, acellular dermal matrix (ADM) is emerging
as a disruptive technology in both reconstructive and aesthetic
and Wake Forest allowed KCI to commercialize what became
KCI’s proprietary VAC therapy system. Two years later, the
system was approved by the FDA and launched. Then in 2000,
KCI received approval for Medicare Part B reimbursement for
VAC therapy, making it available to elderly and disabled
homecare patients in the United States. This revolutionary
technology has changed the way many acute and chronic
wounds are treated. Today, KCI’s wound VAC has served
more than 9 million patients worldwide. Its commercial
impact continues to be an example of a disruptive technology.
In 2013, NPWT had the second largest share of the wound
care market, second only to traditional adhesive bandages24
(Fig. 33.3), meaning many of the prior industry leaders have
been displaced by this new competitor.
NPWT, also referred to as vacuum-assisted wound closure,
applies continuous intermittent sub-atmospheric pressure to
the surface of a wound (Fig. 33.4). Several potential mecha-
nisms have been proposed to explain how NPWT works.
One proposed mechanism is that it reduces wound edema.
By removing this transudative and exudative fluid, NPWT
improves oxygenation to cells. NPWT also diminishes media-
tors of the inflammatory response. In humans, it has been
shown to decrease matrix metalloproteinase. MMPs inhibit
angiogenesis by generating inhibitors such as angiostatin and
endostatin.25 NPWT is also thought to act via mechanotrans-
duction; the conversion of mechanical stimulus into chemical
activity. In vitro, the mechanical deformation increases human
fibroblast growth and migration and in animal models of
wound closure, the mechanical deformation correlates to
increased collagen organization and expression of vascular
endothelial growth factor and fibroblast growth factor.26,27
These modifications of a wound’s microenvironment make it
more conducive to wound healing.
NPWT is being used to treat a spectrum of wounds includ-
ing acute wounds, diabetic wounds, open abdominal and
sternal wounds, pressure ulcers, and in conjunction with
grafts and flaps. However, high quality evidence supports its
use over conventional techniques, most clearly in the setting
of diabetic foot wounds. When compared with wet to dry
dressing changes in diabetic foot ulcers, NPWT reduces time
Fig. 33.3  Global wound care market share, 2013.
Global wound care
market share
2013
Growth factors
4%
Film dressings
4%
Antimicrobial dressings
12%
Traditional adhesive
bandages
29%
Negative pressure
wound therapy
16%
Traditional gauze
bandages
11%
Foam dressings
8%
Non-adherent
bandages
9%
Hydrocolloids
7%
Fig. 33.4  Negative pressure wound therapy.
Improved perfusion
Fluid exudate removal
Reduction
in edema
Granulation tissue
formation

646
CHAPTER 33 • Technology innovation in plastic surgery: A practical guide for the surgeon innovator
“leader” which was implant-based reconstruction with partial
or total muscle coverage (Fig. 33.6). Similar to NPWT, ADM
has been adopted prior to data to support its superiority to
traditional methods. Its adoption may be attributed to ease of
use and meeting surgeon needs that include a quick way to
reconstruct the inframammary fold.
ADM is also largely replacing the use of synthetic meshes
in contaminated abdominal wall defects. These bioprostheses
are thought to incorporate into contaminated tissue without
becoming infected.49 This is an important competitive advan-
tage when compared to synthetic mesh, which is contraindi-
cated in this setting. There still remains a question of the
longevity of mechanical integrity ADM provides in abdominal
wall reconstruction. However, because ADM has met the need
for a large fascial substitute that can be used in the setting
of a contaminated wound, many plastic surgeons quickly
adopted this new technology, despite these unanswered ques-
tions. Interestingly, by embracing ADM-based abdominal
wall reconstruction, plastic surgeons are expanding their role
among general surgeons in this arena.
Like other disruptive technologies, this emerging technol-
ogy lacks long-term follow-up, familiarity, and a complete
safety profile. However, it is a soft-tissue substitute that needs
not be harvested, thus fills a principle need of the reconstruc-
tive surgeon. This technology may thus go on to expand its
indications, supersede other synthetic technologies, and
replace more invasive reconstructive options of the present.
Noninvasive body contouring
The push towards noninvasive medical interventions is an
important force driving the patient–consumer market for
medical intervention. At its inception over three decades
ago, liposuction itself was a large step in a less invasive
form of body contouring compared with traditional surgical
approaches. The introduction of liposuction, like other enabling
technologies, served as a platform for the continued introduc-
tion of refining innovations. The Fischers first introduced sharp
suction techniques for fat removal in 1974. Illouz then refined
the technique with the introduction of high power negative
pressure suction connected to blunt tip cannulas as well as the
Fig. 33.5  Acellular dermal matrix.
A
B
C
D
Donated skin
Epidermis removed
Cells removed
Freeze-dried
Fig. 33.6  ADM is emerging as a disruptive innovation in implant-based breast
reconstruction.
Submuscular coverage
“Industry leader”
ADM
“New competitor”
Time
Market share
ADM: a disruptive innovation in implant-based breast reconstruction
surgery. ADM is a dermal graft in which the dermis is sepa-
rated from the epidermis and all cellular elements, to avoid
tissue rejection and graft failure (Fig. 33.5). The dermal matrix
then acts as a scaffold that permits tissue regeneration
with revascularization and repopulation with fibroblasts. The
ADM is thought to incorporate into surrounding tissue and
eventually be replaced with host collagen.41
Its use has been described in the burn literature for over 20
years; initially as a substitute, and now as a complement to
skin grafting. In the field of breast surgery, ADM was first
described in revision aesthetic cases to address rippling and
symmastia.42,43 In 2005 it was introduced in reconstructive
breast surgery as a tool for direct-to-implant reconstructions.44
In 2007 its use in two-stage breast reconstruction with a tissue
expander was described.45 ADM is used to provide additional
coverage of implant-based reconstructions, support for faster
inferior pole expansion, as well as assistance with precise
placement of the inframammary fold.46,47 Overall, studies still
conflict on its risk profile for postoperative breast complica-
tions. A retrospective analysis of 415 immediate implant-based
breast reconstructions showed that ADM is associated with
high rates of postoperative seromas and infection.48 ADMs,
however, are used in over 60% of implant-based breast recon-
structions. In this market ADM has disrupted the prior

647
Innovations in plastic surgery
development of the “wet technique” used for hydrodissection
to assist with fat removal.50 In the 1980s, Dr. Jeffrey Klein
introduced the tumescent technique that had an important
impact on the safety and efficacy of liposuction. The high
volumes of diluted lidocaine and epinephrine decreased the
need for general anesthesia and minimized blood loss.51
To address surgeon fatigue and improve effectiveness,
especially in more fibrous areas, several refining innovations
have been introduced, none of which have made a significant
change in this field.52 Ultrasound-assisted liposuction (UAL)
was developed by Zocchi in the 1980s. Ultrasonic waves were
introduced to rupture adipocytes creating microcavitations of
liquefied fat. Controversy exists as to whether UAL reduces
complications or improves efficacy when compared with
traditional techniques.53,54 Similarly, power and laser-assisted
lipolysis were refinements to traditional liposuction that have
not shown significant differences in clinical outcomes.52
Focused ultrasound body contouring is a recent innovation
that introduces a potentially new frontier in body contouring
that may or may not prove to be efficacious. This technology
uses focused ultrasound energy delivered through a hand-
held probe (Fig. 33.7). The ultrasonic waves are focused in the
subcutaneous fat, causing permanent disruption of fat cells
with the aim of not damaging the epidermis, dermis, or
underlying tissues and organs. The disrupted adipocytes are
then supposed to be metabolized by the liver. The procedure
is a change from prior refinements, as it requires no incisions
or injections. This technology is not FDA approved for use in
the United States. Small preliminary clinical trials and use
outside of the United States have demonstrated safe and effec-
tive treatment in small areas.55–57 Since its inception in the
1970s, liposuction has proven to be an enabling technology
that continues to serve as a platform for numerous refining
technologies.
Fig. 33.7  Noninvasive body contouring.
Focused ultrasound
therapeutic transducer
Ultrasound imaging
transducer
Low energy everywhere
except in the focal area
Skin
Fat
1. Riskin DJ, Longaker MT, Gertner M, et al. Innovation in surgery: a
historical perspective. Ann Surg. 2006;244:686–693.
2. Gurtner GC, Rohrich RJ, Longaker MT. From bedside to bench and
back again: technology innovation in plastic surgery. Plast Reconstr
Surg. 2009;124:1355–1356. In 2005 Dr. Longaker and Dr. Rorich
highlighted innovation as the competitive advantage of the plastic surgeon.
We then expanded on this concept by discussing the adoption of new
technologies as an important determinant of the advancement of various
fields within surgery.
3. Longaker MT, Rohrich RJ. Innovation: a sustainable competitive
advantage for plastic and reconstructive surgery. Plast Reconstr
Surg. 2005;115:2135–2136.
5. Zenios S, Makower J, Yock P, et al. Biodesign: The Process of
Innovating Medical Technologies. Cambridge: Cambridge University
Press; 2010. These authors designed their textbook as a template to teach
innovation and entrepreneurship. They detail the biodesign process used
by Stanford University’s interdisciplinary Biodesign group. This
three-phase approach involves identifying a medical need, inventing a
device or service, and implementing its use.
6. Cosgrove DM. Developing new technology. J Thorac Cardiovasc Surg.
2001;121(suppl 4):S29–S31.
14. United States Patent and Trademark Office. <
patft/index.html>. Publically available resources for searching patents,
free of charge, include the United States Patent and Trademark Office
Official Site. Additional resources include, but are not limited to, the
searchable databases of all published US patents, available at:
and
21. U.S. Food and Drug Administration. Database of devices with existing
510(k) approval. <
cfPMN/pmn.cfm>. The U.S. Food and Drug Administration also
has an informative and publically available website at:
MedicalDevices/default.htm.
23. Kaplan AV, Baim DS, Smith JJ, et al. Medical device development:
from prototype to regulatory approval. Circulation. 2004;109:3068–
3072. Thomas Fogarty’s expert opinion is provided in this review of
medical device development. The complexity of device approval in the
United States is discussed and identified as a delay in the introduction of
new devices into clinical practice in contrast to the process in Europe.
47. Spear SL, Parikh PM, Reisin E, et al. Acellular dermis-assisted
breast reconstruction. Aesthetic Plast Surg. 2008;32:418–425.
Access the complete reference list online at

647.e1
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highlighted innovation as the competitive advantage of the plastic surgeon.
We then expanded on this concept by discussing the adoption of new
technologies as an important determinant of the advancement of various
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16. Saxenian A. Regional Advantage: Culture and Competition in Silicone
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17. Feldman MP, Florida R. The geographic sources of innovation:
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18. Owen-Smith J, Powell WW. To patent or not: faculty decisions and
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19. Powell WW, Owen-Smith J. Universities and the market for
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20. FDA. 21 USC 360.
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cfPMN/pmn.cfm>. The U.S. Food and Drug Administration also
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22. Chai JY. Medical device regulation in the United States and the
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25. Greene AK, Puder M, Roy R, et al. Microdeformational wound
therapy: effects on angiogenesis and matrix metalloproteinases in
chronic wounds of 3 debilitated patients. Ann Plast Surg. 2006;56:
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26. Jacobs S, Simhaee DA, Marsano A, et al. Efficacy and mechanisms
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1331–1338.
27. Nishimura K, Blume P, Ohgi S, Sumpio BE. Effect of different
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28. Andros G, Armstrong DG, Attinger CE, et al. Consensus statement
on negative pressure wound therapy (V.A.C. Therapy) for the
management of diabetic foot wounds. Ostomy Wound Manage.
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29. Armstrong DG, Lavery LA, Abu-Rumman P, et al. Outcomes of
subatmospheric pressure dressing therapy on wounds of the
diabetic foot. Ostomy Wound Manage. 2002;48:64–68.
30. Armstrong DG, Lavery LA, Diabetic Foot Study Consortium.
Negative pressure wound therapy after partial diabetic foot
amputation: a multicentre, randomised controlled trial. Lancet.
2005;366:1704–1710.
31. Blume PA, Walters J, Payne W, et al. Comparison of negative
pressure wound therapy using vacuum-assisted closure with
advanced moist wound therapy in the treatment of diabetic foot
ulcers: a multicenter randomized controlled trial. Diabetes Care.
2008;31:631–636.
32. Eginton MT, Brown KR, Seabrook GR, et al. A prospective
randomized evaluation of negative-pressure wound dressings for
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33. Etoz A, Kahveci R. Negative pressure wound therapy on diabetic
foot ulcer. Wounds. 2007;19:250–254.
34. Ford CN, Reinhard ER, Yeh D, et al. Interim analysis of a
prospective, randomized trial of vacuum-assisted closure versus the
healthpoint system in the management of pressure ulcers. Ann Plast
Surg. 2002;49:55–61, discussion.
35. McCallon SK, Knight CA, Valiulus JP, et al. Vacuum-assisted closure
versus saline-moistened gauze in the healing of postoperative
diabetic foot wounds. Ostomy Wound Manage. 2000;46:28–32, 4.
36. Kanakaris NK, Thanasas C, Keramaris N, et al. The efficacy of
negative pressure wound therapy in the management of lower
extremity trauma: review of clinical evidence. Injury. 2007;38
(suppl 5):S9–S18.
37. Barendse-Hofmann MG, van Doorn L, Steenvoorde P.
Circumferential application of VAC on a large degloving injury on
the lower extremity. J Wound Care. 2009;18:79–82.
38. DeFranzo AJ, Argenta LC, Marks MW, et al. The use of vacuum-
assisted closure therapy for the treatment of lower-extremity
wounds with exposed bone. Plast Reconstr Surg. 2001;108:1184–1191.
39. Mandal A. Role of topical negative pressure in pressure ulcer
management. J Wound Care. 2007;16:33–35.
40. Wanner MB, Schwarzl F, Strub B, et al. Vacuum-assisted wound
closure for cheaper and more comfortable healing of pressure sores:
a prospective study. Scand J Plast Reconstr Surg Hand Surg. 2003;37:
28–33.
41. Menon NG, Rodriguez ED, Byrnes CK, et al. Revascularization of
human acellular dermis in full-thickness abdominal wall
reconstruction in the rabbit model. Ann Plast Surg. 2003;50:523–527.
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implant-related problems. Plast Reconstr Surg. 2003;112:1692–1696,
discussion 7–8.
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44. Breuing KH, Warren SM. Immediate bilateral breast reconstruction
with implants and inferolateral AlloDerm slings. Ann Plast Surg.
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dermis and tissue expansion in postmastectomy breast
reconstruction. J Plast Reconstr Aesthet Surg. 2007;60:1214–1218.
46. Salzberg CA. Nonexpansive immediate breast reconstruction using
human acellular tissue matrix graft (AlloDerm). Ann Plast Surg.
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breast reconstruction. Aesthetic Plast Surg. 2008;32:418–425.
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49. Candage R, Jones K, Luchette FA, et al. Use of human acellular
dermal matrix for hernia repair: friend or foe? Surgery. 2008;144:
703–709, discussion 9–11.
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51. Klein J. The two standards of care for tumescent liposuction.
Dermatol Surg. 1997;23:1194–1195.
52. Mann MW, Palm MD, Sengelmann RD. New advances in
liposuction technology. Semin Cutan Med Surg. 2008;27:72–82.
53. Howard BK, Beran SJ, Kenkel JM, et al. The effects of ultrasonic
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improve the appearance of body contours: multiple treatments in
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contouring by non-invasive transdermal focused ultrasound. Lasers
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57. Teitelbaum SA, Burns JL, Kubota J, et al. Noninvasive body
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Reconstr Surg. 2007;120:779–789, discussion 790.

34 
Robotics in plastic surgery
Amir E. Ibrahim, Karim A. Sarhane, and Jesse C. Selber
SYNOPSIS
■ This chapter details the recent history of innovations in robotic plastic
surgery. Clinical applications are described and discussed. Future
perspectives for the growth and dissemination of this field are outlined.
■ Robotic technology is the next step in the evolution of minimally
invasive techniques, adding enhanced precision and visualization,
augmenting the capabilities of plastic surgeons, and aiding in achieving
more precise interventions.
■ The robotic interface has provided the necessary exposure and picture
clarity through high-resolution, three-dimensional optics and the
precision instrumentation to accomplish minimally invasive muscle
harvest, including microvascular pedicle dissection, without additional
skin incisions.
■ With improved visualization, elimination of physiologic tremor, motion
scaling, and decreased fatigue, the surgical robot has emerged as a
potentially useful tool in microvascular, microlymphatic and
microneural surgery.
■ Trans-oral robotic surgery (TORS) has been shown to be a reasonable
alternative to chemoradiation treatment for many tumors of the
hypopharynx. Reconstructive techniques using the robot to access
oropharyngeal anatomy has allowed more of these defects to be
reconstructed without splitting the mandible and thus have extended
the indications for TORS.
■ The intrinsic features of robots, including superhuman precision, high
definition, three-dimensional optics and minimally invasive capabilities,
have enabled plastic surgeons to perform minimally invasive
approaches to procedures never before possible.
■ The application of the robotic platform to microsurgery is growing
owing to the development of new microsurgery-specific robotic
instrumentation. As more microsurgeons use the robotic platform, an
increasing number of manufacturers will be driven to design improved
tools for microsurgical procedures.
Introduction
The word “robot” was first introduced to the English language
and to science fiction in 1921 by Karel Čapek in his play
Rossum’s Universal Robots; it is a term derived from the Czech
word robota, which means “forced labor”.1 Since then, robots
have assumed an increasingly significant role in both industry
and medicine. It was the National Aeronautics and Space
Administration (NASA) and the US Army who initially pro-
moted the concept of robotics in surgery after their develop-
ment of telepresence surgery (operating remotely) for use in
wartime and for space applications.1
The history of robotic surgery began with Puma 560
which was first used by the neurosurgeon Kwoh to achieve
improved absolute positioning accuracy for CT-guided ste-
reotactic brain surgery.2 Three years later, Puma 560 was
used by the urologist Davies to perform a transurethral
resection of the prostate.3 This platform led to the develop-
ment of the PROBOT, a robotic system specifically designed
for transurethral resection of the prostate.4 At the same time,
orthopedic surgeons were also taking advantage of robots’
greater precision; they developed a system that could assist
in total hip arthroplasty (preparing the human femur for
artificial hip replacement).5 The RoboDoc system (Integrated
Surgical Systems, Inc., Sacramento, CA) was eventually
developed and used to prepare the femoral canal for pros-
thesis placement; RoboDoc was the first surgical robot
approved by the FDA.6
Based on the promise of surgical robotics, several other
systems have been researched, and then commercially devel-
oped and approved by the FDA to integrate various fields.
These included the Automated Endoscopic System for
Optimal Positioning (AESOP) system (Computer Motion Inc.,
Santa Barbara, CA), a voice-activated robotic endoscope, and
the comprehensive surgical robotic systems, Zeus (Computer
Motion Inc., Santa Barbara, CA) followed by da Vinci (Intui-
tive Surgical Inc., Mountain View, CA).7
The da Vinci platform is a so-called “master–slave” system,
meaning that robotic arms are controlled remotely from a
console in which the surgeon sits and performs the surgery.
The da Vinci system is composed of three components: a
vision tower that holds a dual light source and dual 3-chip
cameras, a master console where the operating surgeon sits,
  Access video content for this chapter online at expertconsult.com

649
Robotics in plastic surgery
invasive resection of oropharyngeal malignancies has wit-
nessed the return of surgery as a primary treatment modality
for such tumors.13,14 Trans-oral robotic surgery (TORS) offered
the possibility of achieving loco-regional tumor control while
avoiding the need for mandibulotomies and chemoradio-
therapy, optimizing both oncologic and functional outcomes.
The reconstructive challenge created by these minimally
invasive resections is that the cylinder of the oropharynx
remains almost entirely closed, severely restricting its access
when attempting to inset and contour vascularized tissue. The
anatomic region between the uvula and the epiglottis is par-
ticularly difficult to approach without a mandibulotomy or a
wide pharyngotomy. Trans-oral robotic reconstructive surgery
(TORRS),15 whether using free flaps, local flaps, or primary
closure, allows access to this difficult anatomy to facilitate
suture approximation and achieve the goals of reconstruction:
preservation of a competent velopharyngeal sphincter, a
watertight seal between the pharynx and neck, adequate
sensation and volume in the tongue base, and optimization of
the physiological function of the oropharynx and larynx.16,17
Set-up involves positioning the patient-side cart at about 60°
from the head of the bed. A mouth retractor is used to establish
the interdental opening and the endoscope and two instru-
ment arms are passed into the mouth, converging to the target
anatomy (Fig. 34.2).
The “remote center” of the instruments is the virtual, three-
dimensional point around which the instruments’ pivot is
placed at the level of the mouth opening to minimize move-
ment around the teeth. Complex manipulation of tissue,
including delicate suturing, can then be performed. This
approach appears to be a superior option in select cases, and
also holds promise in expanding the indications for minimally
invasive reconstructive procedures. Combining trans-oral
robotic flap inset with manual inset through the pharyngotomy
defect is also possible. In these cases, however, it is important
to note that a pharyngotomy is considerably smaller than the
wide pharyngotomy traditionally required for accessing such
tumors, since access to the upper pharynx is achieved roboti-
cally rather than through the neck. The senior author has
documented the value of TORRS for challenging defects of
the head and neck, and has shown both the feasibility18 and
effectiveness19 of this reconstructive method. In addition, by
taking this approach, plastic surgeons are able to provide a
and a moveable, patient-side cart, where two instrument arms
and the camera arm are mounted8 (Fig. 34.1).
Robots have been used in a variety of minimally invasive
surgeries, including cholecystectomies, mitral valve repairs,
radical prostatectomies, reversal of tubal ligations, in addition
to many gastrointestinal surgeries, nephrectomies, and kidney
transplants.7 Advantages are many as robots were able to
overcome the shortcomings of laparoscopy, and have made
possible surgeries that were previously technically unfeasible.
These benefits include increased dexterity, improved visual-
ization, restoration of proper hand–eye coordination, elimina-
tion of physiologic tremors, ability to scale motions, seven
degrees of freedom, and an ergonomic surgeon positioning.9
Robotics in plastic surgery
Inspired by the success of robotics in these other surgical
specialties, the senior author (JCS) began investigating the use
of robots in plastic surgery in 2003. Over the subsequent
10 years, three applications of robotics in plastic surgery
were developed: (1) trans-oral robotic reconstructive surgery
(TORRS) for head and neck reconstruction, allowing complex
oropharyngeal reconstruction without dividing the lip or
mandible; (2) robotic microvascular, microneural, and micro-
lymphatic anastomoses, extending the capabilities of the
human hand to “supra-human” precision; and (3) minimal
access muscle harvest for an “incisionless” harvest of both the
latissimus dorsi and rectus abdominis muscles. In this chapter,
we present the clinical experience of robotic surgery in
those areas.
Trans-oral robotic reconstructive surgery
(TORRS) (Video 34.3 )
Malignant lesions of the oropharynx and base of tongue
remain a prevalent and challenging entity to treat. The fre-
quent need for debilitating surgical procedures (lip and
mandible splitting) to resect such tumors has led to the use
of primary chemoradiation therapy as an alternative treat-
ment.10,11 However, toxicity rates following such approach
were considerably high and functional status was not
improved.12 The advent of robotic surgery for minimally
Fig. 34.1  The full da Vinci Si HD surgical system
(from right to left): an imaging cart, a mobile cart
with four articulated arms, and a console for the
surgeon to control the robot arm (reprinted with
permission from Intuitive Surgical, Sunnyvale, CA).

650
CHAPTER 34 • Robotics in plastic surgery
Fig. 34.2  Trans-oral robotic reconstruction requires a
mouth retractor to set the interdental opening. The
robotic endoscope and two robotic instrument arms
are introduced through the mouth and converge on
the target oropharyngeal anatomy. External view (A)
and depiction of internal view (B) is shown. (From
Selber JC, Sarhane KA, Ibrahim AE, Holsinger FC.
Transoral robotic reconstructive surgery. Semin Plast
Surg. 2014;28:35–38.)
A
B
reliable reconstructive support for the head and neck surgeon
to robotically resect larger, deeper, and more complex tumors
that would be very challenging to reconstruct through tradi-
tional methods.
Indications for TORRS application are still not completely
defined. Longfield et al. recently proposed an algorithm for
the use of TORRS based on tumor site, tumor extent, and
patient-specific factors.20
Robotic microsurgery (Video 34.1 )
One of the most promising applications of robots in plastic
surgery is microsurgery. With complete tremor elimination
and up to 5 : 1 motion scaling, the surgical robot is capable
of superhuman levels of precision. In no area is this precision
more important than in microsurgery. Furthermore, with
its high-definition three-dimensional optics and up to 10×
magnification, robots provide a nearly ideal platform for
performing delicate microvascular manipulations. Robotic
microsurgery was first investigated in a rat model where it
showed a significantly slower time to anastomosis versus
conventional microsurgery, with no difference in technical
failures or patency rates.21 A more recent objective study
compared 30 standard and 31 robot-assisted anastomoses,
and showed excellent patency rates for both methods, but a
significantly longer time for robotic cases.22 In contrast, Katz
et al. showed a learning curve that resulted in a decrease of
robotic anastomotic time from 67 to 20 minutes.23 Morita et al.
reported a quantitative assessment of robotic versus freehand
tasks in a microsurgical setting; a simulated deep and super-
ficial surgical field was created and robot assistance was more
successful for the deep microvascular tasks.24
In the senior author’s initial series of trans-oral robotic
reconstruction of oropharyngeal defects,19 the robot was used
to perform the microvascular anastomoses. The facial artery,
which is the most common recipient artery, is found passing
beneath the hypoglossal nerve and digastric sling, often high
under the body of the mandible. If a tracheostomy and ven-
tilator tubing is also connected, the space available to perform
the anastomosis may be limited. The robot’s precision and
visualization in confined spaces makes it well suited for
anastomoses in such cases. Similarly, Song et al.17 used the
robot for microvascular anastomosis of a radial forearm flap
(recipient vessel: facial artery) to reconstruct the defect created
by resecting a tonsillar tumor (T3 N0 M0, stage III); the neck
dissection was performed through a retro-auricular incision.
In this type of approach, the authors also stated it is more
difficult to perform the micro-anastomosis through the narrow
space using a conventional microscope. Set-up for robotic
microsurgery is relatively straightforward. The robotic arms
are placed at about 45° above the target anatomy and in direct
proximity to the external incision (Fig. 34.3) (Video 34.5
).
A third arm with a “fine tissue forceps” attachment serves
as a stationary assistant, and the surgeon is able to toggle back
Fig. 34.3  Robotic lymphovenous bypass. The robotic camera is positioned in the middle, and the two arms are on either side of the forearm (A). Lymphovenous bypass
completed (B).
A
B

651
Robotics in plastic surgery
muscle, phrenic nerve, scalene muscles, and nerve roots from
C4 to C7). A complete dissection and full exposure of the
supraclavicular portion of the brachial plexus was success-
fully achieved. They were also able to graft a nerve segment
into an artificially created gap by performing separate epi-
and perineural repairs with 10-0 nylon.
Finally, it is worth noting that new directions for robotic
microsurgical applications are being explored in the field of
urology. These include robotic-assisted vasectomy reversal,
sub-inguinal varicocelectomy, denervation of the spermatic
cord, and testicular artery re-anastomosis (in case iatrogenic
injuries occur). Parekattil et al.29 presented their experience
with these techniques and concluded that the use of robotic
assistance in microsurgical vasovasostomy may have benefit
over conventional techniques in decreasing operative
duration and significantly improving early semen analysis
measures. As for robotic-assisted microsurgical subinguinal
varicocelectomy, this technique appears to be feasible, and
there are potential advantages in decreasing operative dura-
tion and improving surgeon efficiency.
Robotic microvascular anastomosis is a burgeoning appli-
cation whose future in microsurgery is promising. Preliminary
results suggest that surgical robots could play a key role in
microsurgery in the future.28,30–32 The current limitations of the
robotic platform for microsurgery include inferior optics of
the endoscope compared to the operating microscope, instru-
ments that are clumsy compared to fine microsurgical instru-
mentation, and lack of haptic (sensory) feedback. Only one
study has objectively assessed haptics and concluded it was
not crucial to completing an accurately tied knot with a
microsurgical suture.33 Subjects tied knots and tightened them
with eyes open and closed with robotic assistance. No differ-
ence in suture breakage and poor tightening was observed.33
The senior author’s experience is that microsurgery is 90%
visual, and most of what we imagine we are feeling, we are
actually seeing, and our brain is supplying the illusion of
sensation. The 10% of haptic feedback that is real, however, is
a very important component and, at this time, constitutes a
barrier to robotics playing a more active role in microsurgery.
In addition, the robotic endoscope is limited in both its clarity,
resolution and magnification compared to the optics of more
traditional operating microscopes. These differences can be
overcome with better quality, fixed distance lenses fitted to
the stereoscopic optical system of the robot. More delicate
instruments are required which bear greater resemblance to
traditional microsurgical instruments and would accommo-
date basic forms of haptic feedback (see below).
Robotic muscle harvest: latissimus dorsi and
rectus abdominis (Videos 34.2 and 34.4 )
Free and pedicled muscle flaps have been in use by plastic
surgeons for a variety of applications since World War I, and
remain work horses in scalp, extremity, head and neck, and
breast reconstruction. Harvest of muscle flaps traditionally
requires incisions that provide access to muscle origin, inser-
tion and pedicle ranging from 20 to 40 cm in length. These
donor sites are conspicuously located on the abdomen and
back, and are a source of morbidity in the form of poor
cosmesis, discomfort, seroma and hernia. Because of the
desirability for minimally invasive harvest, endoscopic and
laparoscopic techniques have been attempted, but have not
and forth between arms 1 and 3, depending on which arm is
being used to position the vessel, and which is being used to
suture. Black Diamond Micro Needle drivers (Intuitive Surgi-
cal) replace the larger jawed needle drivers used during the
inset, and a 9-0 nylon suture is used for the anastomosis.
The main highlights of robot-assisted surgery (ultra-
precision and 100% tremor filtration) are currently being
expanded to the field of super-microsurgery, specifically to
lymphedema surgery. Lymphaticovenular bypasses are gen-
erally performed end-to-end using 11-0 or 12-0 nylon sutures
on a 50-µm needle.25 These are extremely technically challeng-
ing cases, and in certain cases exceed the limits of human
precision. The supra-human precision afforded by the robot
can be of great benefit in this setting. The senior author has
performed several lymphovenous bypass surgeries using the
da Vinci platform and found it to be promising for this appli-
cation. In addition, the robotic platform allows rapid transi-
tioning of the visual system between near-infrared laser
visions (when using indocyanin green to identify lymphatics)
to normal bright field vision, which is a great advantage for
lymphatics surgery when identifying lymphatic vessels using
physiologic flow.
The advantages of robotics over endoscopy (disappearance
of physiological tremor, three-dimensional vision, high defini-
tion, magnification, and superior ergonomics) have led to its
use for microneural and brachial plexus surgery. Nectoux
et al.26 demonstrated the feasibility of robotic microneural
repair in their experiments on fresh nerves (rat thigh sciatic
nerve, pig upper limb median nerve, and human wrist median
nerve, human wrist ulnar nerve, and human finger collateral
nerve) using either an anatomical (epiperineural repair) or a
neurotrophic technique (nerve regrowth guide). Repairs were
all performed without any damaging movements. They con-
cluded that the robot allows very safe and precise peripheral
nerve repairs by counteracting physiological tremor and
improving the overview of the surgical field.
These promising results allowed them to use the robot for
intraneural dissection of peripheral nerve tumors.27 The
robotic approach permitted, in addition to a minimally inva-
sive approach, a higher degree of precision, allowing identi-
fication of the fascicles with greater accuracy and safety.
The brachial plexus is composed of a complex web-like
array of nerves and several intertwined connections, making
it a very intricate anatomical environment which poses great
surgical challenges. Access to the brachial plexus traditionally
requires a long incision, with significant dissection, and
this often results in substantial scarring and adhesions.
For this reason, the traditional approach has been to treat
closed injuries with watchful waiting. However, this can
lead to a delay in exploration of 3 to 6 months post-injury.
Although endoscopic approaches could mitigate the cost of
early exploration by reducing incisional morbidity, the tech-
nique does not allow finely tuned microneural repairs. A
minimally invasive approach with three-dimensional (3D)
high-definition, high-magnification vision allows early explo-
ration of the brachial plexus to diagnose the injuries and
perform higher quality microneural repairs without the open
incision. Facca et al.28 have presented their experimental and
clinical experience in robotic-assisted surgery of the shoulder
girdle and brachial plexus. In their cadaveric studies, they
were able to dissect the supraclavicular brachial plexus
and adjacent anatomical structures (jugular vein, omohyoid

652
CHAPTER 34 • Robotics in plastic surgery
oncologic resection or wound debridement. Inferiorly based
flaps are used to reconstruct abdominopelvic defects where
either space obliteration or visceral protection is needed:
abdominoperineal resection, radical cysto-prostatectomy,
pelvic exenteration, and coverage of major vessels or visceral
repairs. Harvest of the muscle for free tissue transfer can also
be performed robotically, and indications are primarily scalp
and extremity, as in the traditional approach. We observed
several key advantages associated with the robotic approach
for this surgery. As outlined above, the rectus muscle is tradi-
tionally accessed through long incisions to free its origin and
insertion. With the assistance of the robot, these are reduced
to ports, with less risk of wound complications and improved
cosmesis. Maintaining the integrity of the anterior rectus
sheath resulted in a minimal incidence of hernias and bulges.
Overall, less tissue violation is required, and this has resulted
anecdotally in markedly reduced postoperative pain and
patient discomfort, shorter length of hospital stay, and more
rapid functional recovery. Finally, this procedure can easily be
combined with other pelvic procedures. This is of great value
to a complex, multi-disciplinary robotic surgery program
where large resections are being performed without a lapa-
rotomy (Fig. 34.5).
In sum, robotic muscle harvest techniques are safe and
effective, and have a place in the practice of reconstructive
surgery.
Limitations of robotic surgery
Cost
Cost presents the commonly discussed obstacle to routine use
of the robot in plastic surgery. The current cost of the da Vinci
system is $2.2 million and annual maintenance is $138 000.
This cost has been accepted by hospitals in anticipation of
increases in patient volume and reputational benefit. The
determinate of whether a robotic practice is profitable is the
contribution margin per case. This is calculated by subtracting
the cost per case from the revenue per case. For most cases,
revenue from a robotic case is the same as the open procedure,
fixed by the professional fee charged by the doctor and the
hospital fees, based on the DRG (there are no special robotic
surgical codes). For robotic procedures, OR cost may be higher
due to instrumentation, staffing levels and OR time, particu-
larly if the procedure takes longer when done robotically. On
the other hand, hospital costs may decrease if minimally
invasive robotic procedures are associated with shorter
lengths of stay and lower complication rates. The balance of
revenue and cost per procedure will determine if the robotic
procedure is cost effective. In our institution (MD Anderson
Cancer Cancer), a robotic latissimus dorsi (LD) harvest costs
an additional $800 to $900 as compared to an open LD flap.44
Although at first glance cost seems to be a substantial draw-
back for the widespread application of the robot, when
considering the advantages offered in terms of decreased
morbidity and hospital length of stay, robotic-assisted proce-
dures might compare favorably to traditional approaches.44
Prospective long-term studies are needed to objectively assess
the cost-effectiveness of this new technology in terms of
operative time, recovery period, hospital length of stay, and
morbidity rates.
achieved broad acceptance due to technical challenges related
to exposure, retraction and lack of appropriately precise
instrumentation.34–36 The robotic interface has supplied
the necessary exposure and picture clarity through high-
resolution, three-dimensional optics, and the necessary preci-
sion instrumentation to accomplish both muscle and pedicle
dissection. For this reason, robotic muscle harvest holds excel-
lent promise in reducing donor-site morbidity for these
common reconstructive procedures. The senior author has
designed and refined the technique to harvest both the latis-
simus dorsi and rectus abdominis muscles.
Robotic harvest of the latissimus dorsi muscle flap was
developed in a cadaver model in 2010.37 It was first used
clinically in 2011 in a series of 8 patients,38 and has since been
used in over 40 latissimus harvests at the senior author’s
institution. It is a safe procedure with diminished donor-site
morbidity and no major complications. The approach involves
a short axillary incision, or simply use of the existing mastec-
tomy incision or sentinel lymph node incision, two additional
ports, and insufflation. The entire muscle can be harvested
and transposed through the small incision, and has many uses
as a free and pedicled flap, including partial breast reconstruc-
tion and implant coverage, as well as free flap applications.
Over the past two years, this harvest technique has been
gaining popularity among breast reconstruction surgeons as
it proved to be a feasible technique that allows adequate
coverage of the breast providing a reliable reconstruction with
hidden incisions. The technique has been performed world-
wide. Its major indications include reconstruction of lateral
defects following partial mastectomy, implant-based recon-
struction following nipple–areola complex sparing mastecto-
mies, and in secondary reconstruction in patients with
expanders who received adjuvant radiotherapy (delayed-
immediate protocol). Additionally, it can be used for chest
wall deformity correction in patients with Poland syndrome.39
The operative procedure is discussed in detail elsewhere.40 A
novel gasless technique using an articulated long retractor to
maintain an adequate working space and enable latissimus
dorsi muscle dissection (without gas insufflation) was also
recently described.39 In addition to improved cosmesis, the
robotic approach demonstrates reduced patient discomfort,
decreased seroma formation and shortened length of stay
compared to the open procedure (Fig. 34.4).
Robotic harvest of the rectus abdominis muscle uses an
intraperitoneal approach, avoiding violation of the anterior
rectus sheath and hence decreasing the incidence of postop-
erative surgical site occurrences.41 The first published report
of robotic rectus harvest was performed on a 30-year-old
woman for a lower extremity defect.42 The authors observed
advantages of the robotic approach, including uninhibited 3D
view of the rectus muscle and the deep inferior epigastric
artery (DIEA), dexterity levels similar to human hands, and
a clearer image than traditional laparoscopy. Additionally,
during the dissection it was noted that gravity serves to auto-
retract the muscle and makes the perforators and inscriptions
easier to visualize. The operative procedure is discussed in
detail elsewhere.43 Based on our experience, robotic harvest of
the rectus muscle is a valuable option for plastic surgeons, and
can be performed for many different types of reconstructions.
Indications are classified according to the pedicle supplying
the flap. A superiorly-based pedicled flap is used for the cover-
age of anterior midline chest wall and sternal defects following

653
Limitations of robotic surgery
B
Fig. 34.4  (A) Markings and port placement. The
borders of the latissimus dorsi muscle are marked
according to anatomic landmarks. An axillary
incision is then marked. For breast reconstruction,
the sentinel lymph node incision is used. If a free
flap is planned, then an incision is made that will
facilitate pedicle dissection, dissection of the
subcutaneous space anterior to the muscle, and
placement of a port at the inferior end. Two
additional ports are marked 8 cm from the end of
the axillary incision and anterior to the muscle and
8 cm distal to the second port and anterior to the
muscle. (B) After port placement, the robotic side
cart is positioned posterior to the patient with the
two robotic arms and the endoscope extending
over the patient in proximity to the ports.  
(C) Transposition of latissimus dorsi muscle
underneath a subcutaneous skin bridge.
(D) Latissimus dorsi muscle achieves total muscle
coverage over a permanent silicone shaped
implant. (E) 90-cm2 scalp defect from resection of
a squamous cell carcinoma. (F) Three weeks
postoperatively, his flap is well healed, and he is
marked for radiation simulation. (G–H) Case of
immediate breast reconstruction following a right
nipple–areola complex-sparing mastectomy.
Besides a very minor contour defect, there is little
appreciable difference in the appearance of the
donor site before (G) and after (H) surgery.
(A,B,E,F from Selber JC, Baumann DP, Holsinger
FC. Robotic latissimus dorsi muscle harvest: a case
series. Plast Reconstr Surg. 2012;129:1305–1312.
C,D,G,H from Clemens MW, Kronowitz S, Selber
JC. Robotic-assisted latissimus dorsi harvest in
delayed-immediate breast reconstruction. Semin
Plast Surg. 2014;28:20–25.)
A
C
D
E
F
G
H
Robotic training in plastic surgery
Another important question affecting broader application of
robotic-assisted surgery is learning curve. When operating the
robot, a comprehensive understanding of its mechanics,
kinetics, and operative dynamics is a major prerequisite; basic
functionality alone is not enough. Therefore, a significant
amount of time and energy should be spent on learning the
subtle nuances of the robotic mechanics to be able to trouble-
shoot the machine when it is not performing optimally.

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CHAPTER 34 • Robotics in plastic surgery
long. In this regard, simulation centers might be a better
medium for acquisition of robotic surgical skills. In such set-
tings, trainees can use surgical robots to practice operations
on three-dimensional, virtual-reality visual simulations and
soft-tissue models that recreate the textures of human tissues
through force feedback (haptics).45,46 Furthermore, trainees
can be supervised through tele-mentoring. This approach has
the potential to considerably improve the learning curve of
robotic surgery, allowing trainees to acquire robotic skills in a
relatively shorter period while minimizing surgical errors and
Appropriate teaching modules and evaluation and credential-
ing systems for specific plastic surgical skill sets do not yet
exist despite much technological advancement. Surgical train-
ing curricula have stayed more or less the same for more than
a century. Residents and fellows have always learned surgery
through “supervised trial and error” on patients. This method
makes training completely dependent on the case load; it may
even prolong surgical training in some cases. Such an approach
cannot be extended to robotics as current caseloads are very
limited; this makes the learning curve for robotic surgery very
Fig. 34.5  (A) Markings and port placement. The
contralateral costal margin and iliac crest are
marked along a line connecting the anterior axillary
line and the anterior superior iliac spine. The
midpoint between these two landmarks and 2 cm
lateral to it is the desired location of the 12-mm
camera port. On either side of the camera port is
the planned location of the two 8-mm instrument
ports. (B) All three ports are in place and the robot
is ready to be docked. (C) Docking the robot. The
surgical robot is brought into position
perpendicular to the patient on the ipsilateral side
to the muscle being harvested. (D) The dual-
console system. Instruments can be passed from
one surgeon to the other for teaching purposes and
the teacher can “telestrate” on the screen so the
learner can be guided. (E) After having an exposed
and infected arthroplasty endoprosthesis, this
patient received a robotically harvested rectus
muscle to cover the prosthesis. (F) The donor site.
The scars are three small incisions on the
contralateral side to the muscle being harvested.
(G) After having an exposed medial ankle, this
patient also received a robotically harvested rectus
muscle flap. (H) The donor site is limited to the
three ports because the muscle can be removed
through one of the ports using a gallbladder bag.
(A–F from Pedersen J, Song DH, Selber JC.
Robotic, intraperitoneal harvest of the rectus
abdominis muscle. Plast Reconstr Surg.
2014;134:1057–1063. G,H from Ibrahim AE,
Sarhane KA, Pederson JC, Selber JC. Robotic
harvest of the rectus abdominis muscle: principles
and clinical applications. Semin Plast Surg.
2014;28:26–31.)
A
C
E
G
B
D
F
H