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

Conclusion
Autologous skin grafts are a key foundational technique of plastic surgeons and remain a mainstay of
reconstructive surgery for wounds despite the development of more advanced surgical techniques.
Surgeons may choose between split-thickness and full-thickness skin grafts depending on various factors
including graft characteristics (color match, size, amount of primary and secondary contraction), donor
site availability and morbidity, and recipient site requirements. Once applied to a wound bed, skin grafts
heal by a process of imbibition and revascularization, which is a combination of angiogenic vessel
outgrowth originating in the wound bed, reperfusion of the preexisting graft vasculature, and partial
replacement of the existing graft vessels. To minimize shear forces and fluid collecting at the interface,
both of which can lead to graft loss, skin grafts are typically immobilized during the postoperative period
with bolster dressings, which in recent years are more frequently comprised of negative-pressure wound
dressings. Limitations of conventional skin grafts spur the development of biologic and synthetic skin
substitutes. Although the goal of using skin substitutes for definitive wound coverage remains elusive,
skin substitutes and similar products have established a role in providing temporary wound coverage
and assisting in the healing and preparation of wound beds until definitive coverage can be obtained.
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Questions
1. Which option correctly describes the properties of split-thickness skin grafts compared with full-
thickness skin grafts?
a. More primary contracture, less secondary contracture, more metabolic demand from the graft
bed
b. Less primary contracture, more secondary contracture, more metabolic demand from the graft
bed
c. More primary contracture, less secondary contracture, less metabolic demand from the graft
bed
d. Less primary contracture, more secondary contracture, less metabolic demand from the graft
bed
2. Which combination of biologic events characterizes the stage of plasma imbibition of skin graft
healing?
a. Aerobic metabolism of graft cells, increased metabolic demand of the graft, plasma leak into
the wound bed, and increased graft weight secondary to edema
b. Plasma leak into the wound bed, increased metabolic demand of the graft, microvascular
ingrowth into the graft, and increased graft weight secondary to edema
c. Anaerobic metabolism of graft cells, decreased metabolic demand of the graft, plasma leak
into the wound bed, and acidic pH
d. Anaerobic metabolism of graft cells, acidic pH, decreased weight of the graft secondary to
evaporative losses, and fibrinogen conversion to fibrin at the graft interface
3. What is the primary mechanism by which blood flow is reestablished in a skin graft?
a. Reperfusion of existing graft vasculature by inosculation, a process by which blood vessels
from the underlying wound bed connect end-to-end with existing vessels in the skin graft at the
graft interface
b. Microvascular ingrowth from the wound bed, with a temporary angiogenic response from the
preexisting graft vasculature, which also acts as a conduit for capillary ingrowth
c. Revascularization from the wound bed, with formation of entirely new vascular channels via
angiogenesis within the graft and obliteration of preexisting vessels
d. Temporary angiogenic response within the graft, leading to capillary budding within the
graft, increased expression of matrix metalloproteinases MT1-MMP and MMP-2, and
microvascular growth from the graft to the wound bed
4. A 23-year-old man presents to the emergency department after sustaining full-thickness burns to
the volar fingers of his dominant hand. After debridement, the tendons are exposed, with viable
paratenon. The patient wants to minimize his number of surgeries and time out of work. What is the
best option for resurfacing?
a. Split-thickness skin graft from the anterolateral thigh
b. Application of Integra, with staged application of a split-thickness skin graft from the buttock
c. Application of Alloderm
d. Full-thickness skin graft from the inguinal crease
e. Split-thickness skin graft from the scalp
5. A 65-year-old man with PVD, congestive heart failure, and well-controlled type 2 diabetes is
evaluated for a chronic lower extremity wound. The wound appears to have a well-granulating bed,
and it is not debrided before a split-thickness skin graft from the anterior thigh is applied. What is
the factor most likely to lead to graft failure in this patient?
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a. Peripheral edema secondary to congestive heart failure
b. PVD
c. Type 2 diabetes
d. Quantitative wound bacterial count greater than 105 organisms per gram of tissue
1. Answer: d. Split-thickness skin grafts (containing epidermis and a portion of dermis) experience
less primary contracture, experience more secondary contracture, may experience more pigment
changes, are more susceptible to trauma, and have a lower metabolic demand of the recipient site
wound bed, when compared with full-thickness skin grafts (which contain epidermis and the full
dermis).
2. Answer: c. The first stage of graft healing, the stage of plasma imbibition, is characterized by
fibrinogen conversion to fibrin at the graft interface to facilitate adherence, plasma leak from wound
bed capillaries, increased weight of the graft secondary to edema, anaerobic metabolism and
decreased metabolic demands of graft cells, and an acidic pH of approximately 6.8. Microvascular
ingrowth does not occur until the stage of revascularization.
3. Answer: b. After the stage of plasma imbibition, blood flow to the healing graft is established by
revascularization. Angiogenesis begins within the wound bed, with capillary budding and the
ingrowth of newly formed vessels into the graft tissue. A temporary angiogenic response within the
graft also occurs, with increased expression of matrix metalloproteinases MT1-MMP and MMP-2
allowing lysis of the existing capillaries to connect the graft and wound bed vasculature, leading to
reperfusion of parts of the existing graft vasculature. Preexisting graft vasculature acts as a conduit
for capillary ingrowth and is replaced either partially or fully by host endothelial cells by 10 days
after grafting.
4. Answer: d. To receive a skin graft, a wound bed must have healthy vascularized tissue at its base.
A skin graft is less likely to heal over exposed tendon or bone without paratenon or periosteum. The
increased secondary contraction of split-thickness skin grafts mean that they are not ideal for
resurfacing the flexor surfaces of joint, as they can cause joint contracture and limited range of
motion. This patient wants to minimize his number of surgeries and time out of work; therefore a
staged reconstruction with Integra and a split-thickness skin graft would be more time-consuming
than a one-stage procedure. Alloderm can be used as temporary wound coverage but is only a
dermal skin substitute and the wound would likely still need to be definitively covered with an
autologous skin graft at a later time point.
5. Answer: d. Skin grafts are likely to fail if bacterial loads on the quantitative culture are greater than
105 organisms per gram of tissue. Although peripheral edema, PVD, and type 2 diabetes are all
factors than can contribute to delayed skin graft healing, adequate debridement of the wound
leading to decreased bacterial counts is necessary for successful graft healing.
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References
Ratner, D. Skin grafting: from here to there. Dermatol Clin. 1998;16(1):75-90.
Hauben, DJ, Baruchin, A, Mahler, A. On the history of the free skin graft. Ann Plast Surg. 1982;9(3):242-245.
Chick, LR. Brief history and biology of skin grafting. Ann Plast Surg. 1988;21(4):358-365.
Kanitakis, J. Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatol. 2002;12(4):390-399; quiz 400-391.
Corps, BV. The effect of graft thickness, donor site and graft bed on graft shrinkage in the hooded rat. Br J Plast Surg. 1969;22(2):125-133.
Lindenblatt, N, Calcagni, M, Contaldo, C, et al. A new model for studying the revascularization of skin grafts in vivo: the role of
angiogenesis. Plast Reconstr Surg. 2008;122(6):1669-1680.This 2008 study detailed the development of a mouse model that allowed repeated
intravital microscopy to assess the microcirculation during skin graft healing. They determined that capillary widening in the wound bed appeared at
day 1 after grafting and increased until day 4, while capillary buds and sprouts first appeared at day 2. Blood filling of autochthonous graft capillaries
occurred at day 3, resulting in almost complete restoration of the original skin microcirculation on day 5 through interconnections between the
microvasculature of the wound bed and the skin graft through a temporary angiogenic response.
O’Donoghue, MN, Zarem, HA. Stimulation of neovascularization: comparative efficacy of fresh and preserved skin grafts. Plast Reconstr
Surg. 1971;48(5):474-478.
Converse, JM, Uhlschmid, GK, Ballantyne, DL. “Plasmatic circulation” in skin grafts. The phase of serum imbibition. Plast Reconstr Surg.
1969;43(5):495-499.This classic 1969 paper by Converse et al. defined the phase of serum imbibition, referring to the absorption of serum from the
wound bed after grafting, which replaced the previously accepted plasmatic circulation. Full-thickness skin grafts were excised in rats, weighed prior
to grafting, and re-weighed 1 to 11 postoperative days after grafting. The grafts had a characteristic increase in weight in the first 48 to 72 hours,
followed by a steady decrease, which they hypothesized was due to serum absorption from the wound bed, which was followed by the resolution of the
edema once the graft microcirculation was reestablished.
Pepper, FJ. Studies on the viability of mammalian skin autografts after storage at different temperatures. Br J Plast Surg. 1954;6(4):250-256.
Hinshaw , Miller, ER. Histology of healing split-thickness, full-thickness autogenous skin grafts and donor sites. Arch Surg. 1965;91(4):658-
670.
Clemmesen, T. The early circulation in split skin grafts. Acta Chir Scand. 1962;124:11-18.
Peer, LA, Walker, JC. The behavior of autogenous human tissue grafts: a comparative study. 1. Plast Reconstr Surg (1946). 1951;7(1):6-23.
Rous, P. The relative reaction within living mammalian tissues. VI. Factors determining the reaction of skin grafts; a study by the indicator
method of conditions within an ischemic tissue. J Exp Med. 1926;44(6):815-834.
Wu, X, Kathuria, N, Patrick, CW, Reece, GP. Quantitative analysis of the microvasculature growing in the fibrin interface between a skin
graft and the recipient site. Microvasc Res. 2008;75(1):119-129.
Clemmesen, T. Experimental studies on the healing of free skin autografts. Dan Med Bull. 1967;14(suppl 2):1-73.
Haller, JA, Billingham, RE. Studies of the origin of the vasculature in free skin grafts. Ann Surg. 1967;166(6):896-901.
Birch, J, Branemark, PI. The vascularization of a free full thickness skin graft. I. A vital microscopic study. Scand J Plast Reconstr Surg.
1969;3(1):1-10.
Converse, JM, Ballantyne, DL. Distribution of diphosphopyridine nucleotide diaphorase in rat skin autografts and homografts. Plast Reconstr
Surg Transpl Bull. 1962;30:415-425.
Converse, JM, Rapaport, FT. The vascularization of skin autografts and homografts: an experimental study in man. Ann Surg.
1956;143(3):306-315.
Wolff, K, Schellander, FG. Enzyme-histochemical studies on the healing-process of split skin grafts. I. Aminopeptidase, diphosphopyridine-
nucleotide-diaphorase and succinic dehydrogenase in autografts. J Invest Dermatol. 1965;45:38-45.
Zarem, HA, Zweifach, BW, McGehee, JM. Development of microcirculation in full thickness autogenous skin grafts in mice. Am J Physiol.
1967;212(5):1081-1085.
Lindenblatt, N, Platz, U, Althaus, M, et al. Temporary angiogenic transformation of the skin graft vasculature after reperfusion. Plast Reconstr
Surg. 2010;126(1):61-70.
Knapik, A, Hegland, N, Calcagni, M, et al. Metalloproteinases facilitate connection of wound bed vessels to pre-existing skin graft
vasculature. Microvasc Res. 2012;84(1):16-23.Skin graft vasculature in this mouse model demonstrated a temporary angiogenic response to
reperfusion, which was pruned after several days and exhibited a different morphology than regular sprouting angiogenesis present within the wound
bed. Matrix metalloproteinases were found to be involved in capillary ingrowth and regression, with MT1-MMP expressed predominantly on sprout
tips imparting vessel-to-vessel connections, and MMP-2 around vessel sprouts during sprouting angiogenesis facilitating the degradation of the
extracellular matrix.
Calcagni, M, Althaus, MK, Knapik, AD, et al. In vivo visualization of the origination of skin graft vasculature in a wild-type/GFP crossover
model. Microvasc Res. 2011;82(3):237-245.To determine the origin of skin graft vasculature once healed, a crossover wild-type/GFP skin
transplantation model was created, in which each animal carried the graft from the other strain. This demonstrated a replacement of existing graft
capillaries with vessels from the wound bed in 68% of the vessels overall, with vessel replacement in almost 100% of graft vessels at the periphery of the
graft. These data indicate an early ingrowth of angiogenic bed vessels into the existing vascular channels of the graft and subsequent partial to full
centripetal replacement.
Cassavaugh, J, Lounsbury, KM. Hypoxia-mediated biological control. J Cell Biochem. 2011;112(3):735-744.
Smahel, J. The healing of skin grafts. Clin Plast Surg. 1977;4(3):409-424.
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Medawar, PB. The behaviour and fate of skin autografts and skin homografts in rabbits: a report to the War Wounds Committee of the
Medical Research Council. J Anat. 1944;78(Pt 5):176-199.
Medawar, PB. A second study of the behaviour and fate of skin homografts in rabbits: a report to the War Wounds Committee of the Medical
Research Council. J Anat. 1945;79(Pt 4):157-176 154.
Rudolph, R, Klein, L. Isotopic measurement of collagen turnover in skin grafts. Surg Forum. 1971;22:489-491.
Ohuchi, K, Tsurufuji, S. Degradation and turnover of collagen in the mouse skin and the effect of whole body x-irradiation. Biochim Biophys
Acta. 1970;208(3):475-481.
Brown, D, Garner, W, Young, VL. Skin grafting: dermal components in inhibition of wound contraction. South Med J. 1990;83(7):789-795.
Rudolph, R. Inhibition of myofibroblasts by skin grafts. Plast Reconstr Surg. 1979;63(4):473-480.
Oliver, RF, Grant, RA, Kent, CM. The fate of cutaneously and subcutaneously implanted trypsin purified dermal collagen in the pig. Br J Exp
Pathol. 1972;53(5):540-549.
Ramanujam, CL, Han, D, Fowler, S, et al. Impact of diabetes and comorbidities on split-thickness skin grafts for foot wounds. J Am Podiatr
Med Assoc. 2013;103(3):223-232.
Robson, MC, Krizek, TJ. Predicting skin graft survival. J Trauma. 1973;13(3):213-217.
Brolmann, FE, Eskes, AM, Goslings, JC, et al. Randomized clinical trial of donor-site wound dressings after split-skin grafting. Br J Surg.
2013;100(5):619-627.
Kirsner, RS, Falanga, V, Eaglstein, WH. The biology of skin grafts: skin grafts as pharmacologic agents. Arch Dermatol. 1993;129(4):481-483.
Gielen, V, Faure, M, Mauduit, G, Thivolet, J. Progressive replacement of human cultured epithelial allografts by recipient cells as evidenced
by HLA class I antigens expression. Dermatologica. 1987;175(4):166-170.
Burt, AM, Pallett, CD, Sloane, JP, et al. Survival of cultured allografts in patients with burns assessed with probe specific for Y chromosome.
BMJ. 1989;298(6678):915-917.
Phillips, TJ, Bhawan, J, Leigh, IM, et al. Cultured epidermal autografts and allografts: a study of differentiation and allograft survival. J Am
Acad Dermatol. 1990;23(2 Pt 1):189-198.
Singh, M, Nuutila, K, Kruse, C, et al. Challenging the conventional therapy: emerging skin graft techniques for wound healing. Plast Reconstr
Surg. 2015;136(4):524e-530e.
Kanapathy, M, Hachach-Haram, N, Bystrzonowski, N, et al. Epidermal grafting for wound healing: a review on the harvesting systems, the
ultrastructure of the graft and the mechanism of wound healing. Int Wound J. 2017;14(1):16-23.
Hammer, D, Rendon, JL, Sabino, J, et al. Restoring full-thickness defects with spray skin in conjunction with dermal regenerate template and
split-thickness skin grafting: a pilot study. J Tissue Eng Regen Med. 2017;11(12):3523-3529.
Cuono, C, Langdon, R, McGuire, J. Use of cultured epidermal autografts and dermal allografts as skin replacement after burn injury. Lancet.
1986;1:1123-1124.
Lazic, T, Falanga, V. Bioengineered skin constructs and their use in wound healing. Plast Reconstr Surg. 2011;127(suppl 1):75S-90S.
Pruitt, BA, Levine, NS. Characteristics and uses of biologic dressings and skin substitutes. Arch Surg. 1984;119(3):312-322.
Nyame, TT, Chiang, HA, Leavitt, T, et al. Tissue-engineered skin substitutes. Plast Reconstr Surg. 2015;136(6):1379-1388.
Vig, K, Chaudhari, A, Tripathi, S, et al. Advances in skin regeneration using tissue engineering. Int J Mol Sci. 2017;18(4).
Moiemen, NS, Vlachou, E, Staiano, JJ, et al. Reconstructive surgery with Integra dermal regeneration template: histologic study, clinical
evaluation, and current practice. Plast Reconstr Surg. 2006;117(suppl 7):S160-S174.The healing of the Integra dermal regeneration template was
assessed in 20 human patients using weekly punch biopsies. Four stages of dermal regeneration could be demonstrated histologically: imbibition,
fibroblast migration, neovascularization, and remodeling, and maturation. Full vascularization of the neodermis occurred at 4 weeks.
Molnar, JA, DeFranzo, AJ, Hadaegh, A, et al. Acceleration of Integra incorporation in complex tissue defects with subatmospheric pressure.
Plast Reconstr Surg. 2004;113(5):1339-1346.
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C H A P T E R 7
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Principles of Flap Reconstruction: Muscle Flaps,
Myocutaneous Flaps, and Fasciocutaneous Flaps
Michele Ann Manahan
Key Points
Understand the definition of the term flap.
Understand classifications of types of flaps.
Become familiar with elements of essential clinical decision-making with regard to flaps as treatment
options.
Understand basic procedural elements associated with common flaps.
Increase awareness of and vigilance for pitfalls of flap use.
An understanding of surgical manipulation of vascularized tissue or flaps, and the ability to employ this,
could be considered the defining core competency of plastic surgery. A chapter dedicated to flaps can
only ever be a starting point from which to build a lifetime of learning. This chapter could never be
considered completely comprehensive, because an understanding of flaps requires a thorough
knowledge of basic principles as well as a working knowledge of current popular and successful surgical
techniques, balanced with awareness of more historical flap designs that may still be called into use in
salvage situations. This chapter will begin with a review of high points in the historical chronology of
surgical transfer of vascularized tissue, or flaps. Principles will then be explained as they relate to the
broad categories of flaps. Pertinent clinical examples will be reviewed in these areas as well.
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Patient and Technique Selection
Although the remainder of the chapter will serve to highlight the vast number of flap choices available for
reconstruction, several unifying tenets regarding patient and technique selection remain important. One
must always consider patient factors such as comorbidities, nicotine dependence, and local tissue history
(e.g., radiation, trauma, previous surgery) in preoperative planning because these may all affect
intraoperative and postoperative outcomes. 1 Optimize nutrition when possible.
Consideration of the reconstructive ladder is also essential. The great variety of flap techniques, and
modern facility with these, makes flap use appealing. One should remember, however, that healing by
secondary intention, primary closure, skin grafting, and other techniques continue to have valid places in
modern reconstruction. Flap selection should also be considered in terms of the size of the flap, recipient
site needs, location of donor site, and potential associated morbidities. Muscle flaps are generally believed
to fill dead space effectively, potentially owing to bulk, blood supply, and stickiness of tissue, although
many authors believe that fasciocutaneous flaps are fully capable of these tasks.
A healthy flap does not obviate the need for appropriate surgical timing, in terms of both overall patient
condition and local wound readiness. Proper debridement and control of infection must be balanced with
the need for coverage of critical structures when considering flap coverage timing. One must also
remember to consider temporizing measures for wound control in situations when preparation of the
donor site is necessary. For example, prefabrication of flaps with pretransfer tissue expansion can
increase the surface area of the transferred tissue, decrease donor site closure difficulty, and thin flaps for
better fit into recipient areas. 1
Understanding of the flap itself is insufficient for adequate use of flaps as surgical treatments. One must
also understand the recipient site needs and interactions between flaps and recipient sites. For example,
recipient site vessel size, orientation, and flow must be considered prior to free tissue transfer. Techniques
including end-to-end anastomoses, end-to-side anastomoses, surgical delays (selective ligation of some
vascularity to augment remaining vascularity), vein grafting and/or loops, retrograde vessel properties,
supercharging, and many others can salvage a suboptimal situation. Alternative techniques need to be
considered preoperatively should an intraoperative failure of the planned flap occur. Patients should be
counseled about the potential use of alternative treatments before they become necessary.
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Historical Classifications
The key defining feature of transfer of a vascularized segment of soft tissue, the most basic definition of a
flap, is maintenance of blood supply. There are many types of vascularity. 2 Esser characterized the
necessity of vascular inflow as well as outflow. 3 McGregor and Morgan defined random versus axial
patterns of blood supply. They described random pattern flaps as without bias in vascular pattern
compared with axial pattern flaps with an arteriovenous system oriented along the long axis. 4 Taylor and
Palmer defined angiosomes, or segments of skin reliably supplied by single source vessels. They further
described that these vessels can approach the skin directly or indirectly through fascial septae
(septocutaneous perforators), perforating through muscle (musculocutaneous perforators), and via choke
vessels between cutaneous and fascial networks. 5 Free tissue transfer with microvascular anastomosis
was described as a separate method of moving tissue by pedicled transfer in the early 1970s. 6,7 Separation
of the target tissue from bulky underlying soft tissue serving as a conduit for the source vessel was first
described as perforator surgery in 1989. 8 Increasing variety of designs based not only on known, named
vessels but also on a free style fashion by deriving vessels from and to nearly any part of the body. 2
We will now review some of the more widely accepted flap classifications pertinent to current practice.
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Contemporary Classification Systems
Muscle Flap Classification
Mathes and Nahai created the most widely used classification for muscle flaps based on pedicle type.
Their classification is reproduced in Table 7.1. These anatomical variations affect arc of rotation, skin
island design, survival of more distal portions of the muscle flap, microvascular utility, and need for
consideration of surgical delay techniques (partial harvest separated by a period of weeks from
completion of harvest of tissue). 9
TABLE 7.1
Mathes and Nahai Classification of Muscle Flaps 9
Type
Vascular Pedicle
Examples
Considerations
I
One dominant
Gastrocnemius, rectus femoris, tensor fascia lata
One main blood supply for flap
II
One dominant,
minor
supplemental
Biceps femoris, gracilis, platysma, peroneus longus/brevis,
soleus, temporalis, trapezius, vastus lateralis
One main blood supply for flap
III
Two dominant
Semimembranosus, rectus abdominis, gluteus maximus
Two, often equivalent, blood supplies for flap
IV
Multiple segmental
Tibialis anterior, sartorius
One main blood supply, necessary to maintain
pedicle for each transferred segment
V
One dominant,
multiple segmental
Pectoralis major, latissimus dorsi
May be based on dominant or multiple
segmental sources
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Myocutaneous Flap Classification
Myocutaneous flaps are most easily considered in a similar fashion to the underlying muscle that serves
as the bridge of vascularity to the overlying skin and subcutaneous tissue. For myocutaneous flaps, the
reliability of the main pedicle is quite important as is the likelihood of musculocutaneous perforators
arising from this pedicle. As Mathes and Nahai also describe in their landmark paper, skin islands most
distal from the vascular source are least likely to be reliable, and certain patterns (types II and IV,
particularly) are known to have the least reliable skin paddles, most particularly distally. 9
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Fasciocutaneous Flap and Perforator Flap Classifications
Thorough understanding of muscle flaps and their vascular anatomy stands as an essential base for
understanding fasciocutaneous flaps. Over time, the evolution of perforator flaps from basic
fasciocutaneous flaps has decreased sacrifice of muscle. The ability to transfer substantial pieces of skin
and subcutaneous tissue on single submillimeter diameter vessels perforating into flap substances from
underlying source vessels has allowed a nearly uncategorizable plethora of flaps to become useful and
popular in modern reconstruction.
Perforator flaps provide greater variety and reliability of skin paddle design because individual
perforators are now routinely able to be identified and dissected as they enter fasciocutaneous islands.
This versatile flap uses tissue from adjacent areas for good color and structural match to the recipient site.
These techniques have made classifications of fasciocutaneous flaps less essential and prone to
overgeneralization, but an understanding of the core anatomical variations as initially described can be
helpful in designing modern flaps. Historically, Cormack and Lamberty described four categories, as
shown in Table 7.2. 10
TABLE 7.2
Cormack and Lamberty Historical Fasciocutaneous Flap Classification 10
Type
Vascular Anatomy
Examples
A
Multiple, codominant fasciocutaneous perforators
Sartorius, upper arm
B
Single, dominant fasciocutaneous perforator
Supraclavicular
C
Single or multiple septocutaneous perforators
Radial forearm flap
D
Inclusion of other structures like bone and muscle along the source vessel
Radial forearm with radius
As discussed in this section, the concept of fasciocutaneous flaps has progressed well beyond this more
basic classification schema. Much debate has occurred in the effort to better classify modern flap usages.
11-15 Building upon the perforator concept, chimeric flaps can be designed to incorporate various flaps and
flap substances (bone, muscle, fascia, skin/subcutaneous fat) based on different perforators coalescing to a
single source vessel.
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Local Tissue Rearrangement
Understanding of perforator flap anatomy expands the standard random pattern local tissue
rearrangement techniques (e.g., bilobed flaps, rhomboids) for wound closure. More recently defined
propeller flaps and keystone flaps utilize perforator anatomy for local tissue rearrangement. Greater
flexibility of flap design allows for accommodation of local tissue laxity and availability.
Insider tip:
Design the skin paddle over perforator hot spots to incorporate dominant or multiple perforators. 1
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Propeller Flap
Described by Hyakusoku et al. in 1991, the propeller flap is an island flap that reaches the recipient site
through an axial rotation. 1,16,17 The propeller flap technique creates a wide exploratory incision near
expected perforator vessel sites, followed by selection of the dominant perforator (supra- or subfascially)
at the optimal pivot point. Perforator location closest to the defect is preferred for wider angle of rotation
to minimize tension on the pedicle. Dissection toward and along the source vessel is performed until
adequate length is obtained for a lazy S-turn without kinking. The flap perfusion should be confirmed
prior to inset with handheld Doppler evaluation. The remainder of the flap skin island can be incised
after perforator dissection to optimize flap rotation. 1,18
Insider tips:
Skeletonizing the pedicle toward the flap can increase pedicle length. 1
Design the skin paddle larger than the defect for tension-free closure, even with postoperative edema. 1
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Keystone Flap
The keystone flap, described in 2003 by Behan, 19 is designed as two opposing V-Y flaps oriented parallel
to the longitudinal axis of the defect, elevated as a single multiperforator fasciocutaneous advancement
flap. Several variations have been described. Centering the flap over the perforators expands the
undermining, and circumferential incision of the deep fascia at the flap margin can increase mobility.
Larger flaps may increase donor site morbidity but may be necessary to accommodate difficult local
tissue environments (e.g., inflammation, previous irradiation/undermining). 1
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Free-Style Flaps and Supermicrosurgery
By applying basic perforator flap techniques, transfer of fasciocutaneous, fascia only, or cutaneous only
components may be accomplished in nearly any part of the body. Technical mastery of the following
critical steps will open the entire anatomy to consideration for tissue transfer as a flap with over 350
known potential perforators for use. 1,11
The technique begins with prediction of existence of perforating blood vessels into the superficial soft
tissue of choice. Certain locations have fairly predictable perforating blood supply (e.g., periumbilical
perforators from the deep inferior epigastric vessel, through the rectus abdominis muscle, and into a
vertical or transversely designed lower abdominal skin island). In these areas, and in areas with less
interpatient reliability of the presence of these perforators, imaging techniques can optimize preoperative
predictability of skin island design. These include handheld Doppler, color duplex scanning, magnetic
resonance angiography, multidetector-row helical computed tomography, and laser angiography. 2
Dissection through the soft tissue of the flap is usually followed by elevation of the underlying soft tissue
known to contain the source vessel. After identification of the perforator or perforators, selective
inclusion of one or several is decided, and these are followed proximally to larger and larger caliber
vessels, considered the source. Depending on the unique characteristics of the recipient site needs, the
proximal dissection can proceed until sufficient pedicle length and size for anastomosis is obtained. 2
Supermicrosurgery is becoming more popular as the aforementioned techniques are considered for
shorter pedicles and smaller-diameter anastomoses with increased magnification and refinement of
microsurgical instruments and skills. Anastomoses of vessels well under 1 mm in diameter permit
preservation of deep fascia and minimize risk to underlying soft tissues such as muscles that require
dissections through their substance to trace to the larger source vessel. 2,20
Donor site size, texture, color, thickness, and pliability can all be optimized with freedom to design flaps
over virtually any part of the body. It is expected that in the future, these techniques may be considered
routine; however, it is still worth noting that at this point, these are considered technically demanding
and best attempted after mastery of more basic perforator flap techniques. 2
Insider tips:
Assessment of perforator adequacy can be determined by preoperative imaging, intraoperative imaging and
Doppler assessment, visual inspection for size and pulsation, and differential temporary vessel clamping with
assessment of end-organ (flap) viability.
Incorporating potential lifeboats such as possible backup perforating vessels, backup skin paddle designs, and
backup flaps and burning bridges to these options as late as possible in the dissection may allow salvage in the
event of an unforeseen and undesirable intraoperative circumstance. 2
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Clinical Examples
Lateral Arm Flap
This flap is most commonly used when thin, pliable tissue is needed and may be harvested as a chimeric
flap with bone. Most of the time, primary closure of the donor site is possible (particularly with skin
paddles less than 5-7 cm in width). Some surgeons consider it a workhorse, whereas others express
concerns about inconsistent perforator anatomy, short pedicle length, small vessel caliber, and
challenging dissection. 21
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Surgical Technique
With the arm across the torso, the deltoid insertion and lateral epicondyle may be palpated and
connected by a line along which septal perforators from the radial collateral artery between the biceps
brachii and triceps can be found with handheld Doppler probe. After marking a skin paddle centered
over these, the posterior incision is usually made first, followed by subfascial dissection and identification
of the perforators that may then be followed proximally. The skin island dissection can then be
completed. 21
Insider tips:
Identify and protect the radial nerve during dissection. 21
The deltoid insertion may also be divided to increase pedicle length as the radial collateral artery courses toward
the brachial artery. 21
The posterior antebrachial cutaneous nerve must be divided but can be used to create a sensate flap. 21
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Radial Forearm Flap
This fasciocutaneous flap provides thin, pliable tissue in most types of bodies. It has been used for many
reconstructive needs (e.g., intraoral, penile/urethral, extremity). Its popularity arises from the ease of
dissection; robust, reliable vascularity; malleability; and ability to support associated tissues such as bone,
tendon, and nerve. 22 The donor site is difficult to hide and may be associated with stigma in certain
populations as it often needs a skin graft (meshed or sheet, with or without dermal support) for closure.
This flap can be used as a sensate flap, in a reversed fashion, as a flow-through flap, as an adipofascial
flap, or with a short segment of partial thickness radius. When harvested with the palmaris longus
tendon, the flap can also be used for functional purposes. Some of the versatility arises from the multiple
venous drainage options, including the superficial system based on the larger cephalic vein and/or the
deep system based on the paired venae comitantes of the radial artery, which are considered to more
reliably drain the radial forearm tissue. 22-24
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Surgical Technique
The skin paddle is outlined on the volar, distal, radial forearm. Incision through the skin, adipose tissue,
and fascia may be performed, elevating these toward the radial artery that runs between the
brachioradialis and flexor carpi radialis in the distal forearm, sending multiple septocutaneous
perforators to the overlying soft tissue. 25 Lateral antebrachial cutaneous nerve, palmaris longus tendon,
and superficial veins may be incorporated in the harvest and followed along their courses prior to
transection. The radial nerve should be protected as should the vascularity of the tendon sheaths so that a
skin graft may be applied. 25
Insider tips:
Check the Allen test prior to flap harvest to confirm a complete arch communication between the ulnar and
radial artery to protect distal perfusion.
A tourniquet is useful, but keep in mind tourniquet times.
Nearby upper extremity flaps to know: Medial arm (introduced by Tagliacozzi in the 1600s), 26 ulnar artery
(less hairy, better postoperative donor site appearance than radial), digital flaps
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Rectus Abdominis, Deep Inferior Epigastric, and Superficial Inferior Epigastric Flaps
The abdomen, specifically the rectus abdominis muscle and the skin supplied by its musculocutaneous
perforators, is a common donor site. Because of its type II, dual blood supply, a superiorly based rectus
flap can be pedicled for upper trunk reconstruction. The more reliable blood supply is the deep inferior
epigastric system entering the inferior aspect of the muscle. This reliably supplies perforators, most
commonly to the periumbilical area, which can be pedicled or free transfer of muscle, muscle and skin
island, or skin and subcutaneous tissue alone. The skin is usually oriented either vertically as a VRAM
(vertical rectus abdominis myocutaneous) flap or transversely as a TRAM (transverse rectus abdominis
myocutaneous) flap. These orientations are also appropriate when used as a perforator flap without
muscle or fascial sacrifice. 27
Sensation can be restored with harvest of branches of thoracolumbar spinal nerves. 28 Skin and adipose
tissue of a large surface area can also be based on the superficial inferior epigastric system, although
reliability of adequate blood vessels in this area is less assured. Flaps are usually harvested as a unilateral
single unit based on blood supply from one rectus muscle or as two flaps, each based on its ipsilateral
blood supply. These flaps are popular for breast and perineal reconstruction, among other uses. 27
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Surgical Technique
Incision of one side of the planned flap is usually accomplished through the subcutaneous fat, and the
tissue is elevated superficial to the anterior rectus fascia (if starting in midline) or fascia of the external
oblique (if starting laterally). Perforators are identified and followed through the fascia and rectus muscle
toward the inferior epigastric vessels’ origins in the groin. When a muscle flap is used, the borders of the
rectus muscle are identified rather than perforators, and the anterior fascia is resected with the muscle.
Care should be given to identification and ligation of the opposite epigastric system (superior epigastric if
deep inferior epigastric vessels are harvested as the pedicle). 27
With perforator flaps, the anterior rectus fascia can often be closed primarily. Some authors choose to
reinforce this with prosthetic mesh or biologic matrix. Harvest of a portion of the rectus fascia and/or
muscle may require more formal abdominal wall reconstruction using the many available techniques
discussed elsewhere in this text. These are important considerations, as abdominal weakness, bulge, and
hernia are the most specific complications associated with this flap. 28
Insider tips:
Islandization of the umbilical stalk provides a more aesthetic donor site, but patients should understand that
harvest of a vertical unilateral skin island may distort the midline.
Preservation of portions of the multiple superficial and deep blood supplies to this tissue (e.g., contralateral
deep system, ipsi or contralateral superficial system) can salvage clinically marginal tissue noted during flap
harvest through additional venous drainage or supercharging.
Nearby trunk flaps to know: Superficial circumflex iliac artery , groin, Rubens flaps (deep circumflex iliac
artery flaps) 29
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Latissimus Dorsi and Thoracodorsal Artery Perforator Flaps
The latissimus muscle flap may be harvested based on multiple medial posterior thoracic intercostal or
lumbar perforators or on the laterally based thoracodorsal pedicle. This arises as a terminal branch of the
subscapular artery off the axillary artery (or occasionally directly from the axillary artery). 30 The
latissimus is a broad, fan-shaped muscle (originating from the posterior iliac crest and lower six vertebrae
and inserting into the humerus to form the posterior axillary fold) 30 that can be useful for many defects
extending as a pedicled flap to the head and neck and anterior trunk and as free tissue transfer anywhere
on the body. 31,32 Its versatility arises from the ease of harvest, large surface area, and long vascular
pedicle. 30 Skin islands may be designed in multiple orientations to address reconstructive needs or to
minimize donor site morbidity. Using perforator techniques similar to that described earlier for deep
inferior epigastric artery perforator flaps, a thoracodorsal artery perforator flap (TDAP) may be harvested
with dissection from the desired skin island, along the preferred perforator and more proximally along
the thoracodorsal source vessel. 30 The TDAP can still provide a long vascular pedicle and large surface
area but decreases potential morbidity and unnecessary bulk. 33 Additionally, the muscle or perforator
flap can be harvested with more than one soft tissue island, splitting the tissue based on the transverse
and vertical branches of the thoracodorsal, or including bone based on the angular branch to the tip of the
scapula.
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Surgical Technique
Positioning is often via lateral decubitus for unilateral harvest and prone for bilateral harvest, but some
authors advocate supine harvest for a TDAP. 30 Technique depends on skin island design and perforator-
or muscle-harvesting technique. Key points include identification of the vascular pedicle when using the
muscle and dissection of this as proximal as possible for greater pedicle length, useful either for pedicled
or free indications. Closure of the donor site with careful use of percutaneous drains, quilting sutures, or
other techniques to minimize seroma is necessary as this donor site has risk for seroma formation.
Shoulder function may be impaired, but many authors support preservation of ability to engage in
activities of daily living. 30
Insider tips:
Consider previous treatment that might interrupt the thoracodorsal pedicle such as axillary dissection. In this
situation, this flap can still be used by relying on blood flow through the serratus branch.
When used in breast reconstruction, it often requires volume supplementation with an implant.
Consider denervating the muscle flap by transecting the thoracodorsal nerve.
Nearby posterior trunk flaps to know: Paraspinous muscle, trapezius, scapular/parascapular flaps
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Gluteal and Superior Gluteal Artery Perforator Flaps
Early descriptions of the gluteal myocutaneous flap occurred in the 1970s, and the perforator flap based
on the superior gluteal artery became widely recognized two decades later. 34,35 The superior gluteal
artery perforator flap harvest is considered technically difficult by many. Lateral decubitus or supine
positioning is recommended. The buttock tissue yields firmer, more septated, and less malleable flaps
than most other areas. Donor scars can be positioned horizontally or obliquely with a lateral translocation
in some patients who demonstrate appropriate perforator anatomy for a better lift of the inferior buttock
and hip. 36 Concern exists regarding donor site scarring, contour, and possible impact on ambulation, but
those who perform many of these flaps report high success. 36-39
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Surgical Technique
Markings and skin island design may be approached variably. One method uses Doppler identification of
perforators one-third to two-thirds of the distance between the posterior superior iliac spine and greater
trochanter with skin island design centered on a line from coccyx to anterior superior iliac spine (ASIS).
Dissection can be beveled away from the flap, particularly deep to superficial fascia to capture more
tissue. The gluteus maximus fascia is incised and either the muscle flap is harvested or the fascia is
elevated off the gluteal muscle (with cautery action parallel to direction of muscle fascicles) to identify the
perforator. Deep to the gluteal muscle, a venous plexus requires exacting dissection. 36
Insider tips:
Careful hemostasis is required deep to the gluteal muscle within the vascular plexus to avoid damage to
surrounding structures or pedicle.
Be prepared for a shorter pedicle or smaller vessel size than with some other flaps.
Nearby gluteal flaps to know: Inferior gluteal artery perforator, lumbar artery perforator flap
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Upper Thigh Flaps: Gracilis, Transverse/Diagonal Upper Gracilis, Profunda Artery
Perforator
The gracilis is a versatile muscle that can be used alone (e.g., to fill perineal defects), with branch of
obturator nerve (e.g., facial reanimation), or with overlying skin (e.g., breast reconstruction). Soft tissue
can be limited, and the flaps necessitate careful management near the femoral triangle to avoid donor site
morbidity, damage to nearby structures, or lymphatic disruption. 27 One must consider potentially poor
donor site scar appearance/position and sensory disturbance, 40 which may be mitigated with careful
technique.
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Surgical Technique
Frog leg positioning is usually adequate. The gracilis is expected to run 2 to 3 cm posterior to the palpable
adductor longus in this position. If required, the cutaneous island is designed transversely from adductor
tendon posteriorly to the buttock crease with the superior incision in the groin/buttock crease (transverse
upper gracilis flap). This can also be designed diagonally (diagonal upper gracilis flap). Slight posterior
translocation and use of a perforating branch of the profunda femoris vessels (usually through adductor
magnus) without use of the gracilis can also be performed (PAP). Width is determined by pinch test. The
skin island may be elevated traveling posteriorly in the subfascial plane to identify the intermuscular
septum between adductor longus and gracilis and its perforators. These vessels may be followed from the
gracilis (usually entering 10 cm distal to the ischium) toward the source medial femoral circumflex
vessels off the profunda femoris vessels, sacrificing the branches to the other thigh musculature. The
gracilis muscle can be isolated, its distal, minor pedicle divided, and the flap harvested. If muscle only is
used, a vertical incision may be used to identify the muscle posterior to the adductor tendon. The scar can
be short, with harvest performed through a tunnel with a counterincision near the tendon at the knee. 40
Insider tips:
Avoid damaging the greater saphenous vein. 27
Resuspend fascia to avoid labial distortion. 27
If performing a PAP flap, superficial dissection posteriorly may help decrease damage to the posterior femoral
cutaneous nerve to the thigh.
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Anterolateral Thigh Perforator Flap
The thigh is a versatile donor site for many types of reconstruction. Muscle, myocutaneous, adipofascial,
fascial, and fasciocutaneous flaps can all be harvested. Functional limitations can be concerning if they
occur, as lower extremity function is important. Techniques should be considered to minimize this. A
common flap with many indications and usually minimal impact on donor site function is the
anterolateral thigh (ALT) flap.
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Surgical Technique
With the patient supine, a line can be drawn from the ASIS to the superolateral border of the patella
(overlying the septum between vastus lateralis and rectus femoris). Another line from the midpoint of
this line to the midpoint of the distance from ASIS to pubic symphysis will approximate the source
vessels’ course (descending branch of lateral circumflex femoral). The perforators are expected at the
midpoint of the vertical line (or between 1/3 and 2/3 of the distance along the line), usually within a 3-cm
radius, and spaced superiorly and inferiorly apart by about 5 cm. 41 The skin island can be designed two-
thirds posterior to the vertical line. Dissection from the anterior flap margin can proceed, initially supra-
or subfascially and then subfascially as the junction between the muscles is approached. The septum can
be divided distally and the muscles retracted away from each other. The descending branch and
perforators are identified; perforators are selected and dissected through the vastus lateralis and followed
proximally. The remainder of the skin island can then be harvested. 41 Skin pinch can be used to
determine skin island, but often recipient needs exceed this, necessitating skin graft donor site closure.
Insider tips:
In the absence of perforators, the same initial incision can become the posterior border of a newly designed skin
island based on perforators through rectus femoris. 41
Preserve motor branches of the femoral nerve, but the posterior femoral cutaneous nerve of the thigh can be
harvested to provide a sensate flap. 41
A proximal perforator is usually larger, adequate in length, and less intramuscular. 41
Nearby lower extremity flaps to know: Sartorius, rectus femoris, vastus lateralis, tensor fascia lata,
anteromedial thigh, posterior thigh, gastrocnemius, soleus, fibula flaps
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Pectoralis Flap
The pectoralis muscle and/or myocutaneous flap was first described in 1968 by Hueston and McConchie
for sternal reconstruction. 42 Ariyan described its uses in head and neck reconstruction in 1979. 43
Although it has remained as the top choice for anterior sternal reconstruction since its description (sternal
wound dehiscence following cardiac surgery), it experienced increased popularity prior to the advent of
routine microvascular head and neck reconstruction; however, its values remain in head and neck
indications as a fast, versatile, and reliable salvage option. 16
The pectoralis muscle is divided into a clavicular portion (originating from clavicle, inserting into
humerus) and the sternocostal portion (originating from sternum and costal cartilages 1-6, inserting into
external oblique aponeurosis). Its blood supply is a Mathes and Nahai type V through the
thoracoacromial artery and perforators of the internal thoracic, intercostal, and lateral thoracic arteries. 9,44
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Surgical Technique
Sternal defects can be covered with unilateral or bilateral advancement based on the thoracoacromial
vessel with routine dissection of the superior, medial, inferior, and lateral borders. This is often necessary
when the intercostal vessels have been used for cardiac bypass grafts or through extensive sternal
debridement. Additional medial translocation can be accomplished through disinsertion from the
humerus, which can usually be accomplished from the midline sternal wound but may require a
counterincision over the humeral head. Often the reconstruction will be performed with dissection of the
muscle from the anterior skin and subcutaneous fat and closure of the muscle flap layer within the
midline bony defect and disparate closure of the skin and subcutaneous fat. However, this anterior
dissection can be spared, allowing for advancement of the muscle, subcutaneous fat, and skin as a single
unit toward midline. Alternatively, a turnover flap based on multiple medial intercostal perforators may
be used to introduce bulky muscle into the anterior sternal wounds. This requires anterior and posterior
undermining, as well as superior, inferior, and complete lateral release of the muscle borders. 16
Insider tip:
Position the arms by the side to facilitate muscle advancement.
For head and neck reconstruction the muscle is usually rotated based on the thoracoacromial pedicle
(should be visualized and protected on the superior/posterior surface of the muscle) and may include a
skin paddle of a variety (over 10 different described approaches) of different designs based medially or
inferiorly, particularly along the inframammary fold. 16 The flap is inset most often using a subcutaneous
tunnel.
Special manipulations can be accommodated. These include double skin paddles, extension based on
inclusion of the rectus fascia and overlying skin, fascial release, clavicular manipulation, or division of the
sternal portion of the flap. This can also be harvested in concert with a deltopectoral flap. 16
Insider tips:
Include a portion of the fifth rib or avascular bone graft for mandibular reconstruction.
Denervation of the muscle can decrease bulk over time. 16
Prepare for distortion of the breast and difficulty with hair growth if used for esophageal or pharyngeal
reconstruction. 16
Nearby flaps to know: Serratus, deltopectoral flaps
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Conclusion
Flaps are essential reconstructive modalities frequently used by plastic surgeons. As techniques evolve,
infinite varieties of tissue transfer emerge. Thorough understanding of basic principles, ability to apply
these in unique situations, and careful assessments of all aspects of patients and their reconstructive
needs are necessary for successful use of this tool.
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Questions
1. The vascular surgery team requests an inpatient consult on a debilitated 74-year-old woman with a
recent history of uncontrolled diabetes who was incidentally noted to have a cold foot upon
admission for mental status changes associated with diabetic ketoacidosis. Past medical history
includes hypertension, hypercholesterolemia, and myocardial infarction treated with three stents
9 months ago. The vascular surgery team completed an urgent femoral popliteal bypass graft with
PTFE graft 9 days ago, but the patient’s wound has separated and dressing changes are currently
being performed with exposed vessels and PTFE with minimal redundancy of soft tissue at the
margins. What is the optimal next step in management?
a. Continue dressing changes, optimize nutrition and glucose control, and allow wound to heal
secondarily.
b. Perform operative debridement and place split thickness skin graft to wound base.
c. Perform operative debridement and perform primary closure with extensive undermining to
decrease tension.
d. Perform operative debridement and perform gracilis muscle rotational flap with split
thickness skin graft.
e. Perform operative debridement and perform latissimus dorsi myocutaneous free tissue
transfer.
2. The orthopedic surgery team requests an inpatient consult for a 24-year-old otherwise healthy
man, 6 days after Gustilo IIIB distal third of the tibia and fibula fractures treated with hardware at
the fracture site. He returned to the operating room for a second look washout procedure 3 days after
injury, and the wound was found to be stable and clean. Free tissue transfer is deemed necessary, but
the patient is extremely concerned about visible scars outside of the ankle from flap reconstruction
when he is at the pool. Which of the following flaps represents the best option in this circumstance?
a. ALT free flap
b. Latissimus dorsi free flap
c. Vertical rectus abdominis myocutaneous free flap
d. Radial forearm free flap
e. Lateral arm free flap
3. A 50-year-old woman is undergoing autologous tissue breast reconstruction at the time of bilateral
skin-sparing mastectomy for breast cancer. As abdominal skin and subcutaneous flaps are being
raised in the abdomen in preparation for a deep inferior epigastric perforator flap, the internal
mammary vein is noted to be extremely small on the left despite proximal dissection. Which of the
following is least likely to allow salvage of abdominal-based reconstruction?
a. Use of thoracodorsal vessels as recipients rather than the internal mammary vessels
b. Use of a rotational transverse rectus abdominis myocutaneous flap based on the superior
epigastric vessels
c. Use of the right distal internal mammary vein in a retrograde fashion as a recipient vein
d. End-to-side anastomosis of the flap vein end into the internal mammary vein
e. Surgical delay of the internal mammary vessels
4. A 65-year-old man with an anterior chest wall defect due to liposarcoma resection undergoes
latissimus dorsi rotational flap reconstruction. Postoperatively, he reports unsightly and
uncomfortable motion of his flap when moving the ipsilateral arm. This result is most likely due to
which of the following?
a. Absence of postoperative complete shoulder immobilization
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b. Failure to divide the thoracodorsal nerve during flap dissection
c. Inadequate security of inset into recipient site
d. Maintenance of insertion into the humerus
e. Fracture of underlying ribs during sarcoma resection
5. A trainee is working on preoperative planning and is marking landmarks and planned incisions
for a gracilis muscle flap harvest for use in facial reanimation. The patient is placed in a frog leg
position and the most prominent longitudinal medial thigh structure palpable through the skin is
which of the following?
a. Gracilis muscle
b. Rectus femoris muscle
c. Adductor longus muscle
d. Sartorius muscle
e. Tensor fascia lata muscle
1. Answer: d. The clinical scenario represents a common situation in which suboptimal patient
factors (i.e., increased age, uncontrolled diabetes, cardiac disease) exist in the setting of exposure of
critical structures (in this case, prosthetic material and large vessels). Careful consideration of all
aspects and weighing of the risks and benefits improves treatment planning for each unique
situation. A gracilis muscle flap would provide bulk to fill dead space, cushioning against external
trauma, and increased quantity of healthy tissue to combat bacterial contamination or infection in the
groin. Risk of prosthetic infection, anastomotic failure, and difficult-to-control, potentially life-
threatening bleeding from femoral vessels would argue against ongoing dressing changes or skin
grafting directly over exposed structures although optimization of patient factors is always ideal.
Although some patients with risk factors for wound healing complications have redundancy for
primary closure, this patient’s minimal redundancy makes this choice less favorable. A debilitated
patient with active, significant medical comorbidities would not be as good a candidate for a free
tissue transfer procedure with likely increased operative length and complexity when a less complex,
good option exists.
2. Answer: a. Any flap donor site will result in a scar. Some donor sites are able to be closed
primarily and are likely less visible than those that require, for example, skin grafting. In this male
patient concerned about pool activities, the ALT donor site can be closed primarily if the size of the
skin island is not large and is most likely to be covered by clothes compared to the other options, i.e.,
latissimus dorsi, VRAM, radial forearm, and lateral arm flaps.
3. Answer: e. Understanding of flap harvest is insufficient for successful use of flaps in surgical
treatment of patients. One must also understand recipient site dynamics and the interactions
between the flap and the recipient site. A surgical delay is not likely a useful technique for internal
mammary vein size augmentation as there is not an alternate blood flow to ligate for increased flow
through the internal mammary vessels. Internal mammary vessels as well as thoracodorsal vessels
are recipient vessels of appropriate reliability and proximity for anastomosis to the usually long deep
inferior epigastric vessel pedicle. Vein grafting could also be used if length is insufficient. The nature
of the blood supply to the rectus muscle uses the superior blood supply in a rotational fashion for
breast reconstruction. Use of retrograde flow in vessels is an established and often successful
technique of flap manipulation. End-to-side anastomoses manage size mismatch between donor and
recipient vessels.
4. Answer: b. The thoracodorsal nerve supplies motor innervation to the latissimus dorsi muscle and
may be divided during pedicle dissection to decrease muscle activity. Complete shoulder
immobilization is not a standard practice after latissimus dorsi flap use. Inadequate inset may move
the flap out of the ideal position in the recipient site over time but is less likely to impact muscle
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activity itself. Division of the muscle tendon to the humerus may be performed, but this is also less
likely to affect motor activity of the muscle itself. Soft tissue tumor resection is not likely to cause
unrecognized fracture of underlying osseous structures.
5. Answer: c. It is important to understand the relationship of the gracilis muscle and adductor
longus muscle as the more prominent structure is the adductor longus; however, the gracilis is more
commonly used for reconstruction as its function is less essential to the lower extremity. The
sartorius, while existing in the medial thigh for a portion of its course, does not run longitudinally
through the thigh’s length and is not a contributor to the main palpable structure. The rectus femoris
and tensor fascia lata muscles do not travel longitudinally along the medial thigh.
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References
Mohan, AT, Sur, YJ, Zhu, L, et al. The concepts of propeller, perforator, keystone, and other local flaps and their role in the evolution of
reconstruction. Plast Reconstr Surg. 2016;138(4):710e-729e.Classic article describing this area.
Wallace, CG, Kao, HK, Jeng, SF, Wei, FC. Free-style flaps: a further step forward for perforator flap surgery. Plast Reconstr Surg.
2009;124(6):e419-426.Classic article describing this area.
Esser, J. General rules used in simple plastic work on Austrian war-wounded soldiers. Surg Gynecol Obstet. 1917;34:737.
McGregor, IA, Morgan, G. Axial and random pattern flaps. Br J Plast Surg. 1973;26:202-213.
Taylor, GI, Palmer, JH. The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br J Plast Surg.
1987;40:113-141.
Taylor, GI, Daniel, RK. The free flap: composite tissue transfer by vascular anastomosis. Aust N Z J Surg. 1973;43:1-3.
Daniel, RK, Taylor, GI. Distant transfer of an island flap by microvascular anastomoses: a clinical technique. Plast Reconstr Surg. 1973;52:111-
117.
Koshima, I, Soeda, S. Inferior epigastric artery skin flaps without rectus abdominis muscle. Br J Plast Surg. 1989;42:645-648.
Mathes, SJ, Nahai, F. Classification of the vascular anatomy of muscles: experimental and clinical correlation. Plast Reconstr Surg.
1981;67(2):177-187.Classic article describing this area.
Cormack, GC, Lamberty, BG. A classification of fascio-cutaneous flaps according to their patterns of vascularization. Br J Plast Surg.
1984;37(1):80-87.
Wei, FC, Mardini, S. Free-style free flaps. Plast Reconstr Surg. 2004;114:910-916.
Hallock, GG. Direct and indirect perforator flaps: the history and the controversy. Plast Reconstr Surg. 2003;111:855-865.
Kim, JT. New nomenclature concept of perforator flap. Br J Plast Surg. 2005;58:431-440.
Blondeel, PN, Van Landuyt, KH, Monstrey, SJ, et al. The “Gent” consensus on perforator flap terminology: preliminary definitions. Plast
Reconstr Surg. 2003;112:1378-1383.
Wei, FC, Jain, V, Suominen, S, Chen, HC. Confusion among perforator flaps: what is a true perforator flap? Plast Reconstr Surg. 2001;107:874-
876.
Teo, KG, Rozen, WM, Acosta, R. The pectoralis major myocutaneous flap. J Reconstr Microsurg. 2013;29(7):449-456.
Hyakusoku, H, Yamamoto, T, Fumiiri, M. The propeller flap method. Br J Plast Surg. 1991;44:53-54.
Pignatti, M, Ogawa, R, Hallock, GG, et al. The “Tokyo” consensus on propeller flaps. Plast Reconstr Surg. 2011;127:716-722.
Behan, FC. The keystone design perforator island flap in reconstructive surgery. ANZ J Surg. 2003;73:112-120.
Koshima, I, Inagawa, K, Urushibara, K, Moriguchi, T. Paraumbilical perforator flap without deep inferior epigastric vessels. Plast Reconstr
Surg. 1998;102:1052-1057.
Chang, EI, Ibrahim, A, Papazian, N, et al. Perforator mapping and optimizing design of the lateral arm flap: anatomy revisited and clinical
experience. Plast Reconstr Surg. 2016;138(2):300e-306e.Classic article to describe this area.
Patel, SA, Pang, JH, Natoli, N, et al. Reliability of venous couplers of microanastamosis of the venae comitantes in free radial forearm flaps
for head and neck reconstruction. J Reconstr Microsurg. 2013;29(7):433-435.
Futran, ND, Stack, BC. Single versus dual venous drainage of the radial forearm free flap. Am J Otolaryngol. 1996;17(2):112-117.
Cha, YH, Nam, W, Cha, IH, Kim, HJ. Revisiting radial forearm free flap for successful venous drainage. Maxillofac Plast Reconstr Surg.
2017;39(1):14.
Ho, AM, Chang, J. Radial artery perforator flap. J Hand Surg. 2010;35:308-311.
Xue, B, Liu, Y, Zhu, S, et al. Total cheek reconstruction using the pre-expanded medial arm flap with functional and aesthetic donor site
closure. J Craniofac Surg. 2018;29(3):640-644.
Patel, NG, Ramakrishnan, V. Microsurgical tissue transfer in breast reconstruction. Clin Plast Surg. 2017;44:345-359.Classic article describing this
area.
Rozen, WM, Ashton, MW, Kiil, BJ, et al Avoiding denervation of rectus abdominis in DIEP flap harvest II: an intraoperative assessment of
the nerves to rectus. Plast Reconstr Surg. 2008;122(5):1321-1325.
Elliott, LF, Hartrampf, CR. The Rubens flap: the deep circumflex iliac artery flap. Clin Plast Surg. 1998;25(2):283-291.
O’Connell, JE, Bajwaa, MS, Schachea, AG, Shaw, RJ. Head and neck reconstruction with free flaps based on the thoracodorsal system. Oral
Oncol. 2017;75:46-53.
Quillen, CG, Shearin, JC, Georgiade, NG. Use of the latissimus dorsi myocutaneous island flap for reconstruction in the head and neck area.
Plast Reconstr Surg. 1978;62:113-117.
Maxwell, GP, Stueber, K, Hoopes, JE. A free latissimus dorsi myocutaneous flap. Plast Reconstr Surg. 1978;62:462-466.
Yang, LC, Wang, XC, Bentz, ML, et al. Clinical application of the thoracodorsal artery perforator flaps. J Plast Reconstr Aesthet Surg.
2013;66(2):193-200.Classic article describing this area.
Fujino, T, Harasina, T, Aoyagi, F. Reconstruction for aplasia of the breast and pectoral region by microvascular transfer of a free flap from the
buttock. Plast Reconstr Surg. 1975;56:178-181.
Allen, RJ, Tucker, C. Superior gluteal artery perforator free flap for breast reconstruction. Plast Reconstr Surg. 1995;95:1207-1212.Classic article
describing this area.
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Hunter, C, Moody, L, Luan, A, et al. Superior gluteal artery perforator flap: the beauty of the buttock. Ann Plast Surg. 2016;76(3):S191-
S195.Classic article describing this area.
Yaghoubian, A, Boyd, JB. The SGAP flap in breast reconstruction: backup or first choice? Plast Reconstr Surg. 2011;128:29e-31e.
DellaCroce, FJ, Sullivan, SK. Application and refinement of the superior gluteal artery perforator free flap for bilateral simultaneous breast
reconstruction. Plast Reconstr Surg. 2005;116:97-103.
Hur, K, Ohkuma, R, Bellamy, JL, et al. Patient-reported assessment of functional gait outcomes following superior gluteal artery perforator
reconstruction. Plast Reconstr Surg Glob Open. 2013:1(5):1-6.
Locke, MB, Zhonga, T, Mureauc, MAM, Hofer, SOP. Tug ‘O’ war: challenges of transverse upper gracilis (TUG) myocutaneous free flap
breast reconstruction. J Plast Reconstr Aesth Surg. 2012;65:1041e-1050e.Classic article describing this area.
Saint-Cyr, M, Oni, G, Lee, M, et al. Simple approach to harvest of the anterolateral thigh flap. Plast Reconstr Surg. 2012;129(1):207-211.Classic
article describing this area.
Hueston, JT, McConchie, IH. A compound pectoral flap. Aust NZ J Surg. 1968;38(1):61-63.
Ariyan, S. The pectoralis major myocutaneous flap: a versatile flap for reconstruction in the head and neck. Plast Reconstr Surg. 1979;63(1):73-
81.
Wei, WI, Lam, KH, Wong, J. The true pectoralis major mycocutaneous island flap: an anatomical study. Br J Plast Surg. 1984;37(4):568-573.
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C H A P T E R 8
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Transplantation Biology and Applications to
Plastic Surgery
Gerald Brandacher and W. P. Andrew Lee
Key Points
Advances in transplant immunology and microsurgical techniques enabled reconstructive
transplantation to evolve from an experimental idea to a clinical reality over the past 2 decades
For select patients, transplantation of vascularized composite allografts (VCA) provides a means to
replace like with like tissue and thus represents the best restorative modality currently available
Both functional and immunological outcomes after upper extremity and face transplantation have
exceeded initial expectations
Minimization of immunosuppression (single drug) and use of alternative regimens have been
successfully realized in favoring the risk-benefit equation
Innovative immunomodulatory and cell-based tolerance protocols have been proven feasible in
translational large animal VCA models and are about to enter the clinical arena
Indications for reconstructive transplantation are rapidly expanding including pediatric patients,
transplantation of functional subunits, and urogenital reconstructive transplants
The idea of transplanting tissues, organs, or even whole-body parts seems to have always been a dream
and one of the wild fantasies of mankind that eventually has developed into one of the greatest success
stories in Medicine of the last century. In particular, in the field of plastic and reconstructive surgery,
transplantation of tissue from one location of the body to another to restore tissue defects is a
fundamental concept. Thus, it is not surprising that the first successful application of this technique to
transplant tissue from one person to another in the form of allogeneic kidney transplant was first
performed by a plastic surgeon. Dr. Joseph E. Murray on December 23, 1954, at the Brigham and
Women’s Hospital in Boston helped usher in the dawn of a new field of organ transplantation. 1 The
constant and new developments in surgical techniques and more potent, sophisticated types of
immunosuppressive agents have enabled us to perform more and more complex types of transplants
over the past 60 years. As a consequence, transplantation has become the treatment of choice for end-
stage organ failure of the liver, heart, lung, pancreas, and kidney, thus allowing longer and better lives for
thousands of patients. These advances also enabled us to continuously improve graft survival rates to
highly acceptable levels across the board for all types of transplants. According to a recent report by Rana
et al. more than 2 million years of lives could be saved in just 25 years of organ transplantation in the
United States alone. 2
It is fitting that these techniques have now more than half a century later returned to the field of plastic
surgery with the development of reconstructive transplantation as the next chapter and a new era in
transplant medicine. However, it is only within the last 2 decades that transplantation of VCAs such as
hand/upper extremity, face, abdominal wall, as well as urogenital organs including penis and uterus
transplants have become a clinical reality and viable treatment option. These modalities represent the
transplantation of composite structures of the human form for reconstructive surgery to fulfill the prime
mandate of Plastic and Reconstructive Surgery to replace and restore devastating tissue defects using like
with like tissue. 3–5 The ability to transfer VCAs through microvascular surgical techniques, restoring form
and function for complex cutaneous and musculoskeletal defects, is revolutionizing the field of
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reconstructive surgery to add another rung to the reconstructive ladder. However, despite all those
advancements, long-term allograft survival in reconstructive transplantation can only be achieved, as for
any other type of solid organ transplant, through the use of systemic immunosuppression with its
associated sequela of organ toxicity, opportunistic infections, and potential for malignant transformation.
Current research on immunomodulation and tolerance induction holds great promise to reduce the need
for long-term high-dose immunosuppression. 6,7 Although reconstructive allotransplantation in humans
is a relatively new area with small numbers of patients, there are reasons to think that new innovations in
immunomodulation and tolerance may come from the field of VCAs. For example, reconstructive
transplant patients are usually not suffering from life-threatening illness or comorbidities, and therefore
the ethical impetus to minimize side effects from immunosuppressive medications is stronger. Also, the
ability to directly and continuously observe a graft that includes a skin component allows for the use of
novel experimental protocols, as rejection will be seen earlier and potentially could be reversed by topical
agents. Finally, the presence of a vascularized bone marrow niche in many VCAs raises the possibility of
unique immunomodulatory strategies, as will be discussed.
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Historical Perspective
Transplantation of allogeneic tissues has captivated human imagination since antiquity and began as the
medicine of mythology with a timeline that spans three millennia. Indeed, Greek mythology and
religious texts are rich with examples of xeno- and allotransplantation. Of note, the concept of
transplantation transcended temporospatial boundaries and has been reported in Egyptian, Chinese,
Indian, and early Christian mythology as early as 2000 bc. 8 Probably the most famous legend highlighting
transplantation is the miracle of the black leg in the third century AD by the two Saints Cosmas and Damian
—twin brothers who replaced the gangrenous leg of a parishioner with the leg of a deceased Ethiopian
Moor. This legend, in particular, describes for the first time a new concept: cadaveric transplantation—
where the body of the dead can help the living.
Experimentation with various types of transplants continued in the following centuries. Although proper
surgical techniques were not available to facilitate successful performance of solid organ transplantation
in those days, the procedure of skin grafting had already been performed for many centuries. In the
second century BC, the Indian surgeon Sushruta pioneered skin grafting and rotational pedicle flaps for
nasal reconstruction and described over a dozen ways to reconstruct ears and lips. His forward-thinking
concepts were compiled in the Sushruta Samhita, which served as the primary treatise on plastic and
reconstructive surgery for centuries. 9 In the 16th century, Gaspare Tagliacozzi emerged as a popular
figure in transplantation, and he, like Sushruta, was a specialist in rhinoplasty. Tagliacozzi successfully
performed nasal reconstruction on a patient who had lost his nose using a flap from the patient’s upper
arm, which represents one of the earliest records of a human autograft. In 1804, the Milanese surgeon
Giuseppe Baronio claimed to perform successful autogenous and xenogeneic skin transplants as well as
free tendon allografts in sheep. Baronio’s contributions are considered fundamental to the field of plastic
surgery and laid the groundwork for research in the fields of both skin grafting and transplant
immunology. Reports of successful allografts began to circulate around the turn of the 19th century, when
the Scottish surgeon, John Hunter, successfully transplanted the testes of a chicken into a hen without
altering the disposition of the hen. 10 These experiments led Hunter to conclude that transplantation is founded
on a disposition in all living substances to unite when brought into contact with each other, one of the earliest
revelations regarding chimerism and allograft acceptance.
At this point organ transplantation was still not technically feasible owing to limitations in suturing
techniques for vascular anastomosis. This obstacle was overcome in 1902 when Alexis Carrel introduced
his vascular anastomosis technique, which unlocked a continuum of research in experimental organ
transplantation. Within the same year, Austrian surgeon Emerich Ullmann performed the first
experimental kidney transplantation in animals in Vienna, which was followed a few years later by
reports of unsuccessful attempts in humans by Mathieu Jaboulay. 8,11
The earliest reliable, documented outcomes of allogeneic and xenogeneic skin grafts in human recipients
were published by Schone in 1912 and Lexer in 1914. Schone and Lexer demonstrated that these grafts
did not survive more than 3 weeks after transplantation. Padgett provided further evidence in 1932, when
he reported rejection of all skin allografts within 35 days in 40 patients. However, Padgett also
demonstrated that skin grafts exchanged between identical twins survived indefinitely. World War II
accelerated progress in allotransplantation. Gibson, a plastic surgeon at the Glasgow Royal Infirmary,
described the accelerated rejection of allogeneic tissue due to the presence of humoral antibodies from
prior exposure to the same allogeneic source, also known as second set rejection, of skin allografts when
treating pilots with burn injuries. Medawar joined Gibson to investigate this phenomenon and, in
combination with Billingham and Brent, laid the foundation of modern immunology. Medawar
concluded that the rejection of human skin allografts is a result of actively acquired immune reactions—
work that was later summarized by Billingham, Brent, and Medawar in their manuscript Actively
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Acquired Tolerance, which became the preeminent treatise on modulating the immune system for
transplantation. 12 In this manuscript, the authors discuss the importance of chimerism for tolerance
induction, noting the development of donor-specific tolerance by injection of donor cells into neonatal
animals. This knowledge of immunology ultimately facilitated the advent of successful solid organ
transplantation.
Prior to the 1950s, outcomes after organ transplantation were poor. However, the incorporation of
Medawar’s findings led 
 Dr. Joseph Murray to perform the first successful living-related kidney
transplantation between identical twins in 1954. 1 Shortly thereafter, a rapid development of new
chemical immunosuppressive agents occurred. The use of drugs such as azathioprine (AZT), 6-
mercaptopurine, and steroids in the 1960s allowed for the success of cadaveric renal transplants in 1962
and paved the way for a new era in solid organ transplantation. 13 Thereafter, many organs were
successfully transplanted for the first time. In 1963, Dr. James Hardy transplanted the first lung at the
University of Mississippi; 1966, the first successful pancreas transplant was performed at the University
of Minnesota; Dr. Thomas E. Starzl performed the first liver transplant in the following year on a 3-year
old child; the first successful heart transplant was carried out by Christian Barnard in 1967, followed by
the first successful bone marrow transplant by E. Donnall Thomas in 1968. 14 A 4-month-old boy who had
Wiskott-Aldrich syndrome received a bone marrow transplant from his sibling that effectively restored
his immune system duplicating Medawar’s animal findings that had previously resulted in immune
tolerance in chimeric mice. In 1972, Jean-François Borel discovered cyclosporine, which further improved
survival outcomes after transplantation enabling the first successful small bowel transplant in 1988 by
Goulet et al. Since then, many potent and more selective immunosuppressive agents have been
developed that controlled acute rejection and prolonged the survival of transplanted organs, which
enabled transplantation to become the standard of care for patients with end-stage organ disease.
Out of these immunologic and surgical innovations, the idea of reconstructive transplantation was being
formulated and as a result human hand transplantation was first attempted in Ecuador in 1964. 8,15
Although the procedure was a surgical technical success, the available immunosuppressive agents at the
time were insufficient to prevent rejection, and the graft was eventually lost.
This failure underscored the previously described immunological challenges of skin transplants between
genetically disparate individuals. As a result, it was felt that the transplantation of any skin-
 bearing
allograft would be an insurmountable hurdle and another attempt was not carried out for over 3 decades.
During this hiatus, accumulating evidence suggested that the skin of a VCA behaved differently than an
isolated skin graft and, therefore, would not be rejected as vigorously. In addition, animal models of
VCAs designed to investigate newer generations of immunosuppressive agents such as calcineurin
inhibitors (CNIs) (e.g., tacrolimus) and antiproliferative agents (e.g., mycophenolate mofetil [MMF])
indicated that the loss of VCAs could now be prevented. 16 These findings paved the way to preforming
the first successful unilateral hand transplantation in September 1998 by a French team led by Prof. Jean
Michel Dubernard. 17 This was followed shortly thereafter by the first US hand transplant in January 1999
and many more around the world since then. 3,5 In the past decade, over 140 hand and upper extremity
transplants have been performed with encouraging functional and immunologic outcomes that have
exceeded all initial expectations. 18 The success of clinical hand transplantation heralded other new eras
for reconstructive transplantation. In November 2005, Dubernard and Devauchelle performed the first
successful face transplant in Amiens, France. 19 Since then almost 40 face transplants have been performed
at multiple centers around the world. 20,21 In addition, many other types of VCAs have successfully been
carried out with highly encouraging outcomes including the transplantation of larynx, trachea,
vascularized knee, femur, abdominal wall, tongue, penis, uterus, as well as individual tissue components
such as peripheral nerve, flexor tendon, and skin. 8,22–25 Although the surgical techniques to perform these
complex procedures have been optimized, broad application of this reconstructive modality is still
hampered by the risks of life-long, high-dose, multidrug, immunosuppression needed to prevent
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rejection. 7 Thus, continued progress in the field of transplant immunology is critical to the continued
success of reconstructive transplantation, as minimization or elimination of immunosuppressive agents is
a key goal in bringing this life-changing procedure to routine clinical applicability. 6 The field of
reconstructive transplantation will become ubiquitous once transplant tolerance can be reliably achieved.
Currently great strides are being made in experimental large animal studies and first clinical trials,
moving ever closer to elucidating the immunological processes that will help overcome these barriers.
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Nomenclature and Definitions
A brief note on nomenclature will help clarify further discussions of transplantation techniques outlined
in this chapter. Certain terms such as transplant, flap, and graft are often loosely used to refer to a VCA.
However, these terms should be used carefully with knowledge of their specific meaning to ensure clear
communication.
Transplantation can be defined as the transfer of tissue or solid organs to another person or to a different
anatomical location in the same person. According to this definition much of what reconstructive
surgeons do can be classified as a type of transplant. However, in its usual medical usage the term
transplantation is used to describe an allotransplant or tissue transferred from a living or deceased
human donor to another genetically not identically human patient. Within this chapter, our discussion of
transplantation will be focused mostly on the topic of allotransplantation, as the transfer of autologous
tissue locally or distantly is covered elsewhere in the text.
A graft is tissue completely separated from its donor bed and moved to a separate recipient bed, with its
survival relying on ingrowth of new vessels from the surrounding recipient tissue. A vascularized graft or
flap either remains attached to its native blood supply or becomes revascularized via microvascular
anastomoses to recipient vessels (aka, free flap). An autograft refers to tissue transplanted from one
anatomical location to another within the same individual. An isograft is tissue transplanted between
genetically identical individuals, such as transplants between syngeneic animals or human monozygotic
twins. An allograft or homograft is tissue transplanted between unrelated individuals of the same species.
A xenograft or heterograft is tissue transplanted between different species.
Transplantation can also be described according to the anatomical site into which the tissue is transferred.
An orthotopic transplant is transferred into an anatomically similar site, whereas a heterotopic transplant is
transferred into a different site from its donor origin. The term reconstructive transplantation is used to
differentiate the transfer of composite tissues such as the hand or face from more traditional solid organ
transplants. However, the issuance of a Final Rule in July 2013 by the United States Secretary of Health
has redefined VCAs as organs rather than tissues and thereby acknowledged the importance of
reconstructive transplantation as a vital treatment option as well as opened up the potential to formalize
policies and procedures, under the auspices of the Organ Procurement and Transplantation Network,
that can improve VCA donation and procurement practices, develop allocation algorithms, and provide
transparent oversight equal to solid organ transplantation. 26
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Transplant Immunology
Three-Signal Model of Alloimmunity
Transplantation of organs or tissues between genetically disparate individuals of the same species leads
to recognition and rejection of the allogeneic tissue by the recipient’s immune system. This alloimmune
response that discriminates between self- and nonself tissues remains the main barrier to successful
transplantation.
The key initiators of an alloimmune response are genetically encoded polymorphic proteins that
constitute graft antigens referred to as major histocompatibility complex (MHC) or in humans are known
as human leukocyte antigens (HLA). The MHC complex is a cell surface molecule (glycoprotein) that is
common to a polymorphic multigene cluster located on chromosome 6 in humans. There are two classes
of MHC molecules, class I and II, that differ in their structure, function, and tissue distribution. MHC
class I antigens consist of two polypeptide chains, an α-chain with a transmembranous domain and the
β2-microglobulin chain that is expressed on all nucleated cells. MHC class II antigens consist also of two
polypeptide chains an α- and a β-chain; however, their expression is restricted to antigen-presenting cells
(APCs) such as dendritic cells (DCs), monocytes, macrophages, some endothelial cells, thymic epithelial
cells, and B lymphocytes. 27 Each MHC has an inherited group of HLA genes or haplotypes: HLA class I
genes known as HLA-A, -B, and -C and HLA class II genes known as HLA-DR, -DP, and -DQ. The HLA
determines the compatibility of all organ and tissue transplants. The primary function of MHC molecules
is to bind short peptides that are derived from proteins processed by the cell. Such non–self-protein-MHC
complexes coordinate the interaction of lymphocytes during the acute and chronic alloimmune response.
There are two main pathways by which host T cells recognize donor alloantigens (Figure 8.1). Following
transplantation, donor APCs migrate toward host lymphoid tissues and can directly activate naïve
recipient T cells. Once T cells are activated, they become effector T cells and migrate to the graft and
mediate rejection. This is aptly named the direct pathway of allorecognition. In contrast to the direct
pathway, recipient APCs play a significant role in the indirect pathway of allorecognition where they take
up, process, and present donor antigens to host T cells. Both pathways of allorecognition are important in
mediating graft rejection; however, the direct pathway is considered to be the main initiator of acute
rejection, whereas the indirect pathway is thought to be of greater significance in the physiology of
chronic graft rejection in the long term. 28
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FIGURE 8.1 T cell recognition of alloantigens. A. Direct pathway, recipient T cells interact with intact allogeneic major or minor
histocompatibility peptide complexes presented by donor APCs. B. Indirect pathway, recipient T cells interact with processed
allogeneic major or minor histocompatibility peptide complexes presented by recipient APCs. APC, antigen-presenting cell;
MHC, major histocompatibility complex.
The initiation of an alloimmune response is a well-orchestrated and choreographed interplay of various
different players of the immune system including DCs, naïve and memory T cells, and B cells. DCs are
key players in the initiation of an alloimmune response post transplant, as they express high levels of
MHC class II and costimulatory molecules essential for T cell activation. 29 Upon activation, DCs of both
donor and recipient origin migrate to the T cell areas of secondary lymphoid organs of the host where
they encounter naive CD4+ T cells and central memory T cells, which recirculate within the lymphoid
tissues. Within the secondary lymph nodes, T cells encounter the MHC alloantigen that is expressed on
the surface of the DCs with their specific T cell receptors (TCRs) combined with the CD3 complex that
facilitates signal transduction. This interaction of MHC, TCR, and CD3 complex is referred to as signal 1
(Figure 8.2). Typically, MHC class I molecules present antigen peptides derived from intracellular sources
to CD8+ T cells, whereas MHC class II molecules present antigen derived from endolysosomal
compartments to CD4+ T cells.
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FIGURE 8.2 Costimulatory blockade. A. Antigen-specific T cell activation depends on T cell receptor-ligand interaction (signal
1) and costimulatory signals (signal 2) for full activation and proliferation. B. Blocking of T cell costimulatory pathways (signal 2)
results in T cell anergy and thus prevents allograft rejection, promotes long-term graft survival, and induces tolerance in various
rodent and nonhuman primate transplant models. APC, antigen-presenting cells; MHC, major histocompatibility complex; TCR,
T cell receptor.
In addition to signal 1, APCs provide so called costimulatory signals to fully activate T cells. These
costimulatory signals are also referred to as signal 2 during T cell activation. Two of the best-characterized
costimulatory signals/pathways in transplantation are the B7/CD28 and the CD40/CD154 pathways. In
addition, there are a multitude of other second signals including 4-1BB (CD137) and 4-1BBL, inducible
costimulator and ligand of inducible costimulator, OX40/OX40L, LFA1/ICAM-1, or PD-1/PDL-1/2 29,30 (see
Figure 8.2).
Once a naïve T cell receives both signal 1 and signal 2 through a single specific APC, three intracellular
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signal transduction pathways are activated including the calcium-calcineurin pathway, RAS-mitogen-
activated protein kinase pathway, and the NF-κB pathway. Through those pathways, several
transcription factors such as NFAT, AP-1, and NF-κB are activated, which subsequently leads to the
expression of cytokine-encoded genes for IL-2, CD154, and CD25. These cytokines, in particular IL-2 and
IL-15, then act via autocrine mechanisms to initiate T cell proliferation and expansion. This final step is
also referred to as signal 3.
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