Plastic Surgery Volume 1 Principles 4th

577
Surgical considerations and treatment
recommended, recognizing that a full 2.0-cm margin may be
difficult to achieve in some areas of functional or cosmetic
significance.124 For lesions >2.0 mm in thickness, a margin of
at least 2.0 cm is recommended.
In determining the extent of the operation, whether on the
face or on the trunk, it is important to consider the impact of
the scar on the patient’s self-image. The Pigment Lesion Study
Group of the University of Pennsylvania evaluated the extent
to which patients were distressed by scars after melanoma
resections.108 The two factors that had a negative impact were
the degree of surgical depression or indentation and the
patients’ preoperative perception of the scar to be expected.
The actual scar length did not have as much of an effect as the
Table 29.7  Trials comparing margin width for cutaneous melanoma
Study; author; year
N
Median follow-up
Lesion thickness
Margins
Local recurrence (%)
10-year overall survival
WHO; Cascinelli N;
1998115
612
12 yr
0–1 mm
1 cm
3/186 (1.6)
87%
1.1–2.0 mm
1 cm
5/119 (4.2)
0–1 mm
3 cm
1/173 (0.6)
87%
1.1–2.0 mm
3 cm
2/134 (1.5)
Swedish; Cohn-
Cedarmark G;
2000118
989
11 yr
0.8–2 mm
2 cm
3/476 (0.6)
79%
5 cm
5/513 (1)
76%
French Cooperative
Group; Khayat D;
2003119
326
16 yr
<2.1 mm
2 cm
1/181 (0.05)
87%
5 cm
4/185 (0.2)
86%
Melanoma Intergroup
Trial; Karakousis
CP; 1996121
468
8 yr
1–4 mm
2 cm
(2.1)
70%
4 cm
(2.6)
77%
British Trial; Thomas
JM; 2004123
900
5 yr
≥2 mm
1 cm
15/453 (3.3)
Not reported
3 cm
13/447 (2.9)
Not reported
(Sources: Sladden MJ, Balch C, Barzilai DA, et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev. 2009(4):CD004835 and
Stone M. Initial surgical management of melanoma of the skin and unusual sites. In: Atkins MB, Weiser M, Tsao H (eds). UpToDate. 18.3 ed. Waltham, MA: UpToDate,
Inc.; 2010.)
Fig. 29.22  Skin grafts provide adequate coverage for wide resections, but they can lead to significant deformities, as demonstrated in the infraorbital region (A) and scalp (B).
A
B
extent of depression of the scar. As such, skin grafts are
acceptable for reconstructions of large resection sites, but they
cause significant deformities (Fig. 29.22), which are usually
avoided with flaps for coverage. The author has previously
reported on the safety of coverage of these wounds with
flaps.125
Head and neck
Although the skin of the head and neck accounts for only 9%
of total body surface area, 15–30% of all primary melanomas
develop on the head and neck.126,127 High-risk melanomas of
the face should be excised as outlined above and closed with

578
CHAPTER 29 • Melanoma
area cannot be resurfaced with a skin flap because it requires
thin pliable covering. Resurfacing is best accomplished by
employing a cheek advancement flap to cover most of the
defect and a full-thickness skin graft to the eyelids. The best
place to harvest this skin graft is from the ipsilateral or contra­
lateral upper eyelid; the postauricular area may be an accept­
able alternative.
In situations where tissue conservation is deemed neces­
sary, frozen section analysis may be considered, but it does
carry a risk of false negative report.128 Additionally, while
investigational, Mohs micrographic surgery may be consid­
ered in these situations, or when treating superficial lesions
of large diameter (e.g., lentigo maligna). Large series report
that Mohs surgery129 may control the primary lesion, but
adjacent flaps. Although resurfacing the resection site with a
skin graft is possible, the cosmetic results are not as acceptable
as with a flap. A local or regional skin flap covers the wound
with a far more satisfactory color match to the rest of the face
than a distant flap (Fig. 29.23).
A difficult area to resurface is a surgical defect over the chin
because this area requires skin that firmly adheres to the
mandible, soft tissue for contour, and a good match of the skin
flap to the remainder of the face. A distant flap simply does
not provide a satisfactory color match. A wide excision of this
area can be resurfaced satisfactorily with an advancement flap
of the neck.
On occasion, the melanoma forms on the upper part of the
cheek, requiring removal of skin from the lower eyelids. This
Fig. 29.23  Melanoma of the cheek (A) was treated with a wide excision of the primary site (B), a complete functional neck dissection (C), and coverage with a large
cervicofacial myocutaneous flap incorporating the platysma muscle (D). One year postoperative photographs (E,F).
A
B
C
D
E
F

579
Surgical considerations and treatment
Melanomas of the toes and feet are usually of the acral
lentiginous type. These tumors spread aggressively and have
a high incidence of local and regional recurrences. Therefore,
they are best treated by aggressive resections (Fig. 29.28). A
significant advantage to the use of flaps in the lower extremity
is that patients may be able to ambulate the day after surgery
and leave the hospital much sooner than patients treated with
skin grafts.
Trunk
Primary melanomas of the trunk may be excised with more
liberal margins (as much as 2–4 cm if need be) and still be
closed easily. Some areas may be closed by wide undermining
and large advancement flaps. Otherwise, these areas may still
be closed readily by one or more local flaps (Fig. 29.29). Deep
fascia and muscle may be preserved if not involved by tumor
invasion.
Lymphadenectomy
The decision to perform a lymphadenectomy in a patient
with melanoma requires further thought. In patients who
present with palpable lymphadenopathy, it is appropriate to
confirm diagnosis with fine needle aspiration, core needle,
or open biopsy of the clinically enlarged lymph node(s). In
the absence of radiological evidence of distant metastases,
wide excision of the primary site and complete dissection of
the involved lymph node basin is indicated. For staging
purposes, the number of positive nodes, the total number of
nodes examined and the presence or absence of extranodal
tumor extension must be recorded.124 Of note, in the lower
extremities, when PET or pelvic CT scans reveal iliac and/or
obturator lymphadenopathy, or if a positive Cloquet’s
longer follow-up is required before widespread adoption of
this technique.130 Treatment of lentigo maligna with imiqui­
mod has also emerged as an effective therapy.131–134 Recent
published work has shown the effectiveness of treating
residual in situ melanoma at the margins of surgical resections
with imiquimod, confirmed with negative biopsies after
adequate treatment.135
Extremities
Thin melanomas of the fingertips may be excised and the
defect reconstructed with volar advancement flaps (Fig. 29.24)
to provide sensate coverage. Melanomas of the nail bed that
are thin can be removed with the underlying periosteum (Fig.
29.25A,B); if the tumor has not penetrated through the peri­
osteum, then the distal phalanx can be saved and covered
with a full-thickness skin graft. Lesions of the finger thicker
than 1 mm are more safely treated with an interphalangeal
joint amputation (Fig. 29.26) or a ray amputation, depending
on the extent of the tumor. Subungual melanoma of the fingers
should be resected at the distal interphalangeal joint to pre­
serve function.136 Similarly, subungual melanomas involving
the toes should be managed with digital amputation at the
metatarsal–phalangeal joint.
Melanomas of the dorsum of the hand, the forearm, and
the leg may be treated more readily with a wide excision.
These surgical wounds have traditionally been covered with
skin grafts with good success. However, coverage of these
wide excisions with local flaps (Fig. 29.27) has been accom­
plished with successful control of the primary site and a more
cosmetically acceptable result.125 Furthermore, these patients
do not need to have the arm or leg immobilized, and they
have a shorter hospital stay than do those who have had
skin grafts.
A
B
C
Fig. 29.24  Melanoma of the fingertip (A) was excised
with the nail, nail matrix, and nail bed (B). The wound
was covered with a volar advancement flap (C,D). The
thumb remained free of disease at 4 years postop (E).
D
E

580
CHAPTER 29 • Melanoma
Fig. 29.25  (A) Thin melanoma of the nail bed. (B) Nail bed and eponychium is removed with the underlying periosteum. (C) Full-thickness skin graft. (D) Healed thumb
nail bed.
A
B
C
D
lymph node is found, deep groin dissection should be
considered.137,138
The majority of patients, however, will present without
clinical evidence of nodal disease, and some will require
sentinel lymph node biopsy (for staging purposes). The deci­
sion regarding which patients should undergo SLNB is
dependent upon the pathological stage of the primary lesion.
As stated previously, SLNB should be considered for patients
with primary melanomas that demonstrate aggressive biology.
Specifically, this includes stage IA melanomas with adverse
prognostic features (i.e., thickness ≥1.0 mm, positive deep
margins, lymphovascular invasion, or young patient age),
stage IB and II melanomas, as well as patients with resectable
solitary in-transit stage III melanoma.124 The decision regard­
ing whether to proceed with SLNB is ultimately up to the
patient and the treating physician, and should be performed
at the time of WLE.124
If the sentinel lymph node is negative, regional lymph node
dissection is not indicated. If the SLN is positive, the patient
should be offered complete dissection of the involved lymph
node basin; 15–20% of these dissections will demonstrate
melanoma in non-sentinel lymph nodes.139,140 It has been
shown that factors related to the SLN can help predict the
presence of melanoma in non-SLNs: size of the metastatic
focus, number of metastatic foci, and extracapsular exten­
sion.141,142 Of note, these stage III patients should be considered
for adjuvant treatment with interferon alfa, especially if they
lack any serious comorbidity and have an otherwise reason­
able life expectancy.
The Multicenter Selective Lymphadenectomy Trial (MSLT)
was a large trial designed to address the role of lymphatic
mapping with SLNB in determining prognosis and its impact
on survival; the third of the five planned interim analyses was
published in 2006.143 The primary study group included 1347
patients with intermediate thickness melanomas (1.2 to
3.5 mm) who were randomly assigned to WLE with observa­
tion or WLE with lymphatic mapping and SLNB. In the
observation group, if palpable nodal metastases became
evident, the patient underwent completion lymphadenec­
tomy. Likewise, in the SLNB group, if the SLNB was histologi­
cally positive, the patient underwent immediate completion
lymphadenectomy. A survival benefit was not demonstrated
for the overall study population randomly assigned to lym­
phatic mapping and SLNB. However, amongst the patients
who had nodal disease, the patients in the observation group
who subsequently developed nodal metastases had more
involved nodes at the time of lymphadenectomy (3.3 vs. 1.4
nodes), and a significantly lower 5-year survival rate (52.4%
vs. 72.3%). Nevertheless, the final report of the MSLT was
published in 2014. There was no significant difference noted
in the 10-year melanoma specific survival in the two groups
in the study population where 20.8% were found to have
nodal metastases and 79.2% had no metastases.144
However, there is no place for the simple excision of the
involved palpable lymph node alone because it is more than
likely that additional lymph nodes have micrometastases.145
This question will be answered by the MSLT-II trial in pro­
gress now. In the meantime, the only accepted treatment is a

581
Surgical considerations and treatment
accessory nerve, internal jugular vein, and sternocleidomas­
toid muscle to provide a more acceptable appearance and
functional neck and shoulder muscles.146
Axillary lymphadenectomy
The patient is placed in the supine position with the arm
abducted and placed freely on two arm boards. The entire
arm, including the hand, is prepared for surgery and draped,
so that the arm can be moved as needed during the procedure.
Make a prominent S-shaped incision with the midportion
placed transversely across the apex of the axilla, with one limb
complete lymphadenectomy of the regional group of lymph
nodes.
Cervical lymphadenectomy
Patients with melanoma of the face and anterior scalp (Fig.
29.30) who are selected for cervical lymphadenectomy because
of positive sentinel lymph nodes should also be considered
for superficial parotidectomy on the ipsilateral side because
the preparotid lymph nodes are the first echelon of nodal
drainage. A cervical lymphadenectomy (Fig. 29.31) can
be performed with or without preservation of the spinal
Fig. 29.26  Thicker melanomas of fingers (A) need to be treated more aggressively
with interphalangeal joint amputation (B) or ray amputation (C–E).
A
B
C
D
E

582
CHAPTER 29 • Melanoma
After the axillary contents are removed, reposition the skin
flaps and suture them closed over large suction catheters.
These catheters remain in place for 3 to 10 days, depending
on the amount of 24-hour drainage accumulated. The decision
to remove the drain should be based on the pattern and rate
of daily decrease in the drainage rather than the actual
amount. The drains are most commonly ready to be removed
by the fifth or sixth day. The patient is instructed to keep the
arm in a sling during waking hours to decrease shearing
forces on the dissected tissues and thereby lessen the
drainage.
Pelvic and inguinofemoral lymphadenectomy
Excision of inguinofemoral lymph nodes is facilitated by a
horizontal incision along the skin crease 2 cm above and
parallel to the inguinal region and a vertical incision over
the femoral vessels, beginning in the inguinal skinfold and
extending inferiorly for 8 to 10 cm. This approach results in
an “interrupted” T incision (Fig. 29.33). Carry the skin incision
in the inguinal area down to the fascia of the external oblique
muscle and split it open to expose the internal oblique muscle.
Dissect this origin of the internal oblique muscle sharply off
descending behind the anterior edge of the lateral border of
the pectoralis major muscle (Fig. 29.32) and the second limb
descending along the posterior border of the upper arm.
Elevate the two opposing skin flaps at the level of Scarpa
fascia to expose the axillary contents.
Identify the brachial vein along the arm and dissect
proximally to the axilla, from the anterior portion of the
upper arm toward the posterior portion. Dissect the entire
axillary contents in this fashion, moving in a distal to proxi­
mal direction. Ligate and transect the branches of the bra­
chial vein; leave the thoracodorsal artery, vein, and nerve
intact, however.
Dissect the axillary contents from along the lateral border
of the pectoralis major muscle, leaving the muscle fascia
behind with the muscle. Free the contents from the posterior
surface of the pectoralis major, which is then retracted to
expose the pectoralis minor. Dissect the fat and lymphatic
contents from behind both the pectoralis major and
minor muscles and retract this material downward. Using a
surgical sponge pad, sweep the axillary contents away from
the chest wall in a caudad direction. This maneuver usually
exposes the long thoracic nerve along the chest wall.
Preserve this nerve.
Fig. 29.27  Wide excisions of melanomas of the hands, forearms, and legs (A) may
be treated with local transposition flaps (B) to allow the patient to use the extremities
early in the postoperative period (C).
A
B
C

583
Surgical considerations and treatment
Fig. 29.28  Melanoma of the plantar area (A) may be resurfaced with an arterial fasciocutaneous flap (B–E).
A
B
C
D
E
A
B
Fig. 29.29  In the truncal area, deep melanomas may be resected widely (A) and still be closed reliably with large transposition flaps (B).

584
CHAPTER 29 • Melanoma
on the surface of the muscle fascia until the saphenous vein
and saphenous bulb are reached on the femoral vein.
Dissect the contents in the inguinal region down to the
fascia of the external oblique muscle and in the caudad direc­
tion to communicate with the femoral dissection. Do not
remove the muscle fascia or transpose the muscles adjacent to
the femoral vessels to cover these vessels; such procedures
increase the risk of lymphedema. Close the wounds over large
suction catheters that remain in place for 3 to 10 days. Patients
are permitted to ambulate the night of surgery or the next
morning.
the iliac crest to provide access to the retroperitoneal space.
Pull the peritoneum away along the undersurface of the
transversalis fascia from the external iliac vessels and lymph
nodes. This provides an excellent view of the nodes for the
pelvic lymphadenectomy.
Elevate the skin flaps on either side of the femoral incisions
at the level of Scarpa fascia as well as the skin below the hori­
zontal incision (Fig. 29.34). Elevate the skin completely from
the inguinal incision to the lower end of the femoral incision.
Dissect the femoral fat and lymphatic tissues down to but not
including the muscle fascia. Continue the dissection cephalad
Fig. 29.30  Melanoma of the vertex of the scalp (A) was found to have lymphatic
drainage to bilateral parotid and cervical nodes (B). The parotid sentinel node
(C) was found to be positive (D). Postoperative healed flaps (E).
A
C
B
D
E

585
Surgical considerations and treatment
A
B
GA
SCM
T
C
SA
IJ
D
SCM
T
BP
Fig. 29.31  Functional radical neck dissection can be performed while preserving the sternocleidomastoid muscle (SCM), the internal jugular vein (IJ), and the spinal
accessory nerve (SA). BP, brachial plexus; GA, great auricular nerve; T, trapezius. (Reproduced from Ariyan S. Radical neck dissection. Surg Clin North Am. 1986;66:133.)

586
CHAPTER 29 • Melanoma
Fig. 29.32  Axillary incision is S shaped (A) to provide opposing flaps for greater access to the axillary contents (B). See text for details.
A
B
A
B
External oblique
Anterior superior
iliac spine
Inguinal ligament
Inguinal nodes
Femoral nodes
Spermatic cord
External iliac
artery and vein
Internal iliac
artery and vein
Rectus sheath
External
iliac nodes
Fossa ovalis
Sartorius
Great
saphenous vein
Fig. 29.33  An “interrupted” T incision (A,B) is used for access to both the inguinal and iliac nodes.

587
Adjuvant treatment for melanoma
The fascia of the external oblique muscle is split (C), and the internal oblique and transversalis are dissected away from the inguinal ligament and iliac
crest. The peritoneum is peeled back by finger dissection (D) to obtain retroperitoneal access to the iliac and obturator nodes (E).
Fig. 29.33, cont’d
C
Anterior superior
iliac spine
Inguinal ligament
Peritoneum
Spermatic cord
Rectus sheath
Internal oblique muscle
External oblique
(retracted)
D
Peritoneum
Internal oblique
(retracted)
Psoas
Femoral nerve
External iliac
artery and vein
E
Adjuvant treatment for melanoma
Wide local excision is the standard of care for early stage
melanoma, and the majority of patients present with stage
I–IIA disease. However, high-risk patients with stage IIB–III
disease have a generally poorer prognosis. These patients
have been the primary focus in development of adjuvant
therapies for melanoma. Over the past 30 years, a number of
efforts with chemotherapeutic agents (e.g., dacarbazine147),
nonspecific immune adjuvants (e.g., BCG vaccine147), and
hormonal agents (e.g. megestrol acetate), have not demon­
strated a benefit over observation or placebo. The most
promising results have been demonstrated with interferon
alfa (IFN-α), an immune modulator that can induce antitumor
activity.
Interferon alfa
Early clinical studies with IFN-α demonstrated modest anti­
tumor activity in patients with metastatic melanoma. A series
of clinical trials were then started to examine the role of
adjuvant IFN-α in patients with high-risk melanoma. Each of
these trials has different doses and schedules, and an optimal
approach to the administration of IFN-α has not been estab­
lished. Review of data combined from multiple randomized
controlled trials demonstrates that IFN-α is associated with
an improvement in relapse-free survival but not with overall
survival.148 The role for adjuvant IFN-α for patients with
intermediate to high-risk melanoma remains undefined.149
Treatment with adjuvant IFN-α should be made on an indi­
vidual basis, after discussion with the patient, with discussion
of the potential benefits and side effects associated with IFN-α

588
CHAPTER 29 • Melanoma
Fig. 29.34  The femoral nodes are approached through a vertical incision over the region of the femoral vessels. After the medial and lateral flaps are elevated (left), the
subcutaneous fat containing the lymph nodes is dissected off the deeper muscle fascia (right).
Inguinal ligament
Superficial
inguinal nodes
Sartorius
Great
saphenous vein
Femoral artery
Femoral vein
Pubic tubercle
therapy.150 For patients with stage IIB through stage III disease
which has been resected, the National Comprehensive Cancer
Network (NCCN) recommends consideration of adjuvant
treatment with IFN-α or enrollment in a clinical trial.124
Radiation therapy
When excision of a primary melanoma with appropriate
margins is not possible, adjuvant radiation may be considered,
though it is not generally recommended for the primary treat­
ment of cutaneous melanoma. In some exceptional circum­
stances, for patients who are poor candidates for surgical
resection, radiotherapy may offer an acceptable alternative for
control of disease. Additionally, successful treatment of ocular
melanoma with eye and vision preservation is one of the
major triumphs of radiation oncology. Very high rates of local
control can be achieved with particle radiation treatment or
episcleral plaque brachytherapy.151
Early studies by Barranco et al.152 demonstrated that cul­
tured malignant melanoma cells differ from other types of
tumor cells in their radiosensitivity. They found that the rela­
tive radioresistance of melanoma could be overcome by
increasing the individual dose fraction. These studies helped
form the basis for clinical practice, and subsequent studies
helped to determine the ideal fraction size and total therapeu­
tic dose that effectively treats melanoma.
In patients with extensive facial lentigo maligna melanoma
that precludes adequate surgical resection based on functional
or cosmetic considerations, radiotherapy has been reported.153
However, more recent advances in topical therapies such as
imiquimod (Aldara®), are supplanting radiation therapy (RT)
in the non-surgical treatment of lentigo maligna melanoma.
Early work by Habermalz and Fischer demonstrated some
success with higher-dose radiotherapy over more frequent
time intervals than conventional radiotherapy, with partial
or complete regression especially seen with subcutaneous
metastases.154 Prospective nonrandomized clinical trials at
M.D. Anderson Cancer Center, treating high risk groups of
melanoma patients with radiation therapy, have helped estab­
lish the basis of treatment with hypofractionated radiation
therapy in melanoma.155 While locoregional control was
improved with adjuvant radiation, distant metastases devel­
oped in a large number of patients (58 of 174 patients).155 Later
studies from this group evaluated the outcome of patients
with clinically apparent cervical lymph node metastases
from malignant melanoma managed with surgical resection
and adjuvant radiation.156 After 10-year follow-up, the group
demonstrated a 94% regional control rate. Radiation-related
complications for the patients were manageable.156 The same
group evaluated the utility of radiation therapy alone in the
treatment of 36 patients with positive SLNB (in lieu of comple­
tion lymphadenectomy), and demonstrated 93% regional
control over five years.157 However, when recurrences present
within radiated fields, the surgical management can be
arduous and lead to breakdown and non-healing wounds.
Work from Australia and New Zealand, including the
Trans Tasman Radiation Oncology Group, has provided the
most meaningful data with respect to the role of adjuvant
radiation therapy in the treatment of metastatic disease.158 In
a prospective study, 250 patients with positive lymph nodes
deemed to be at high risk for locoregional recurrence were
randomly assigned to radiation therapy (48 Gy in 20 frac­
tions) or observation. Patients were considered high risk if
there was extracapsular extension, multiple positive nodes

589
Adjuvant treatment for melanoma
perfusions were tolerated well among our elderly patients,
with no greater risk of complications in this group than in our
younger patients (Table 29.9).169 In general, the major role for
isolated limb infusion/perfusion is palliation of unresectable
limb disease.
(≥1 parotid, ≥2 cervical or axillary, or ≥3 groin-positive nodes),
and large lymph nodes (≥3 cm for parotid, neck, and axilla,
and ≥4 cm for groin location). After a median follow-up of 40
months, the radiation arm showed a significantly lower rate
of lymph node recurrence as compared with observation.
However, there were no differences in relapse-free survival or
overall survival.159 An update presented at the American
Society of Clinical Oncology 2013 meeting with 6-year median
follow-up confirmed these findings. The 5-year local recur­
rence rate was 18% for the RT arm and 33% for the observation
arm (P <0.02), and no difference in relapse-free or overall
survival.160
The NCCN recommends consideration of adjuvant radia­
tion therapy for patients with multiple positive lymph nodes,
lymph nodes with extracapsular spread, nodal recurrence
and in-transit metastases. Additionally, radiotherapy should
be considered after excision of primary melanomas that
demonstrate neurotropism (desmoplastic type),161 as well as
mucosal melanomas, which may or may not be amenable to
complete excision.162,163 Radiation therapy may also be used
for palliative treatment of melanoma distant metastases.
It is effective for pain, mass effect, tumor-related hemor­
rhage, and local irritation from skin and subcutaneous
metastases.164
Isolated limb infusion/perfusion
Tumor recurrences correlate with the thickness of the lesion.
Between 60% and 70% of recurrences appear in the first 18 to
24 months after surgical treatments (Table 29.8; Fig. 29.35).165
It is presumed that the earliest recurrences are to local or
regional lymph nodes, followed by in-transit metastases;
distant metastases appear last.
Patients with local recurrences may be treated with wider
surgical resections, but extensive local recurrences or in-transit
metastases are more difficult to treat. In-transit metastases of
extremities may be treated with isolation-perfusion of that
extremity with melphalan,166 dacarbazine (DTIC),167 cisplatin,
or hypo-osmolar perfusions with carboplatin.168 Carboplatin
eradicated the lesions after perfusion in some patients (Fig.
29.36), whereas the control was temporary in other patients.
The advantage of DTIC is its low incidence of hepatic and
systemic toxicity, which is far less than that after perfusion
with L-phenylalanine mustard. Indeed, we found that such
Table 29.8  Timing of recurrent melanoma after surgical
treatment
Site
18
months
24
months
3
years
5
years
10
years
Nodal
63%
74%
86%
93%
95%
Local
55%
67%
81%
88%
95%
In-transit
55%
67%
80%
90%
97%
Systemic
40%
52%
71%
83%
95%
Overall
57%
97%
81%
90%
95%
(Modified from Fusi S, Ariyan S, Sternlicht A. Data on first recurrence after
treatment for malignant melanoma in a large patient population. Plast Reconstr
Surg. 1993;91:94.)
Fig. 29.35  Patterns and timing of recurrences for melanoma. The
curve of the timing of local recurrence and in-transit metastases
precedes that of lymph node recurrences and distant organ
metastases. (From Fusi S, Ariyan S, Sternlicht A. Data on first
recurrence after treatment for malignant melanoma in a large
patient population. Plast Reconstr Surg. 1993;91:94.)
Interval (in months)
Percent of patients
0
10
20
30
40
50
60
70
80
90
100
0
12
24
36
48
60
72
84
96
108
120
Local
In-trans
Reg. Node
Distant
Table 29.9  Perfusion complications*
Age
20s
30s
40s
50s
60s
70s
80s
Total
Number
4
7
11
9
16
14
6
67
Edema
(pre/post)
1
2
2
1
6
Edema
(post)
1
2
2
5
Seroma
1
1
1
1
4
Wound
1
5
1
2
9
Pulmonary
embolus
1
1
Total
2
0
2
2
9
2
2
19
14/47 (32%)
4/20 (20%)
*67 perfusions in 60 patients, 1976–1995.(From Ariyan S, Poo WJ. The safety
and efficacy of isolated perfusion of extremities for recurrent tumor in elderly
patients. A 20-year experience. Surgery. 1998;123:335.)

590
CHAPTER 29 • Melanoma
months and the 5-year survival rate is approximately 3%.171 A
number of systemic therapy options are available to treat
patients with metastatic disease, including single-agent or
multiple-agent chemotherapy, biochemotherapy, radiother­
apy, or strategies using immune modulation. However, little
consensus exists regarding standard therapy for patients with
metastatic melanoma. From the surgical perspective, if the
patient has metastatic disease localized to a single small focus
Treatment of metastatic melanoma
It is well-established that the prognosis of patients with meta­
static melanoma is poor; those with liver, brain, or bone
metastasis have a median survival of only 6 months. Brain
metastases occur in more than 50% of patients with advanced
melanoma.170 The median survival of these patients is 4.4
Fig. 29.36  Regional isolated perfusion of a lower extremity recurrence (A) led to
significant response and shrinking of the tumor (B is before perfusion, and C is after
perfusion), permitting radical resection of the mass (D) without compromise to the
popliteal vessels. At 1 year, there was no local recurrence (E).
A
B
C
D
E

591
Treatment of metastatic melanoma
melanoma, but the duration of clinical benefit is short (2–7
months).178,179
Tumor vaccines
The development of melanoma-specific tumor vaccines has
been predicated on several clinical observations and lines of
basic investigation that indicate that the immune system can
eradicate melanoma cells. Although a comprehensive review
of available vaccine strategies is beyond the scope of this
chapter, some of the more encouraging studies are reviewed.
Ganglioside GM2, an antigen overexpressed by many
melanoma cells, given in combination with bacille Calmette–
Guérin (BCG) or other immune adjuvants, was developed by
Haughton et al. at Memorial Sloan Kettering Cancer Center.
Initial clinical trials suggested promising results,180 however,
further studies failed to show clinical benefit with this adju­
vant treatment. Kirkwood et al.181 reported their experience
comparing high-dose interferon alfa-2b and GM2 ganglioside
vaccine for patients with resected melanoma, demonstrating
the advantage of interferon. Additionally, a randomized Phase
III trial (EORTC 18961) of adjuvant GM2-KLH21 in 1314
patients with stage II melanoma was closed early by the data
monitoring committee because of inferior survival in the
vaccine arm.182
A polyvalent melanoma cell vaccine, developed at the John
Wayne Cancer Center, was shown to be capable of inducing
humoral and cell-mediated immune responses to melanoma-
specific antigens.183,184 Nevertheless, this vaccine was found
not to be beneficial in a clinical trial. Dr. Steven Rosenberg and
co-investigators at the surgery branch of the National Cancer
Institute have identified other cancer vaccines by using spe­
cific peptide antigens recognized by autologous tumor-specific
T-cell clone reactivity.185 Peptide vaccines are most often
administered with cytokine or cellular immune adjuvants
such as dendritic cells. DiFronzo et al.186 demonstrated that
enhanced humoral responses in patients treated with polyva­
lent vaccines resulted in limited but improved disease-free
survival. It is difficult to advocate any of the current vaccine
strategies over another, and we recommend that patients with
high-risk melanoma be enrolled into prospective trials to test
these therapeutic strategies.
Adoptive T-cell transfer
Rosenberg developed the concept of adoptive T-cell transfer,
whereby tumor-infiltrating lymphocytes (TIL) isolated from
an excised tumor can be expanded in the laboratory and
infused back into the patient. The goal is for these cells to
attack the tumor cells with an increased strength than the
body would otherwise provide. A phase II trial of adoptive
T-cell transfer in patients with stage IV melanoma demon­
strated an objective response in 50% of patients.187
Interleukin-2
Interleukin-2 (IL-2) was approved by the Food and Drug
Administration (FDA) for treatment of metastatic melanoma
in 1998. High-dose intravenous bolus IL-2 treatment resulted
in overall objective response rates of about 17%.188 In a highly
selected patient population (n = 270), IL-2 was able to induce
durable complete responses (median response duration over
59 months) in approximately 6% of patients and partial
in the lung, liver, or brain, it may be worthwhile to consider
resection (Table 29.10). However, multiple recurrences
cannot be treated by surgery and require consideration of
systemic chemotherapy and/or radiation therapy. More
recent advances have shown a very high response rate to
gamma knife treatment of single or few metastases to brain.
Chemotherapeutic agents
Dacarbazine (DTIC) remains a standard of care in community
practice, and has been used as a standard for comparing the
efficacy of new regimens.124,172 Combination chemotherapeutic
regimens that include other cytotoxic drugs, such as bis(2-
chloroethyl)nitrosourea (BCNU), cisplatin, lomustine, and
hydroxyurea, have been reported. The trials comparing DTIC
alone or in combination with other agents have shown a
significant though brief improvement in survival.173 Dacarba­
zine and temozolomide have been shown to have similar
response rates (approximately 10–20%) and survival,174 with
median response duration averaging approximately 3–4
months.173,174 Temozolomide can cross the blood–brain barrier,
making it an attractive agent for treating melanoma, which
has a propensity for metastasis to the brain.
Combination chemotherapy regimens such as CVD (dacar­
bazine plus cisplatin and vinblastine) or the Dartmouth
regimen (dacarbazine, carmustine, cisplatin and tamoxifen)
initially reported higher response rates,175,176 but subsequent
clinical trials have not replicated these high response rates.177
Paclitaxel, alone or in combination with carboplatin, may
provide clinical benefit to some patients with metastatic
Table 29.10  Surgery for metastatic melanoma: outcome
Site of first
recurrence
Incidence
5-year
survival
Median
survival
Skin, fat, lymph
node
50%–60%
5%–40%
8–50 months
Lung
15%–35%
5%–30%
8–20 months
Gastrointestinal
tract
2%–4%
Minority of
patients
10–20 months
  Small bowel
(35%–65%)
Mostly
palliative for
symptomatic
relief
  Colon
(10%–15%)
  Stomach
(5%)
Brain (at
autopsy,
50%–80%)
8%–15%
Unexpected
(5%)
6–8 months
80%–90% have
symptomatic
relief
Liver (rarely
single
metastasis)
5%
Anecdotal
cases
–
(Modified from Allen PJ, Coit DG. The surgical management of metastatic
melanoma. Ann Surg Oncol. 2002;9:762.)

592
CHAPTER 29 • Melanoma
responses in 10% of patients with metastatic melanoma, albeit
with high levels of toxicity.189,190 One study demonstrated
increased response rate in metastatic melanoma when IL-2
was given with the 210M peptide vaccine (22%) compared to
IL-2 (13%) alone.191
Biochemotherapy
Given the individual success of chemotherapeutic agents
and the biologically active agents (IFN-α and IL-2), bio­
chemotherapy regimens were developed. By combining
conventional chemotherapeutic drugs with biologically
active agents, investigators were able to demonstrate modest
improvement in response rates of metastatic melanoma. In
single institutional phase II trials, biochemotherapy (cisplatin,
vinblastine, dacarbazine, interferon alfa, and interleukin-2)
produced an overall response rate of 27–64% and a com­
plete response rate of 15–21% in patients with metastatic
melanoma.192–194 A report of a small phase III randomized
trial comparing sequential biochemotherapy (dacarbazine,
cisplatin, vinblastine with interleukin-2 and interferon alfa
administered on a distinct schedule) with combined cisplatin,
vinblastine and dacarbazine (CVD) showed response rates
of 48% for the biochemotherapy regimen compared to 25%
for CVD alone; median survival for patients treated with
biochemotherapy was 11.9 months vs. 9.2 months for CVD.195
In a phase III randomized intergroup trial (E3695), bioche­
motherapy (cisplatin, vinblastine, dacarbazine, interleukin-2
and interferon alfa-2b) produced a slightly higher response
rate and progression free survival than CVD alone, but it
was not associated with either improved quality of response
or overall survival in patients with metastatic melanoma.196
Biochemotherapy was substantially more toxic than CVD.
Additional attempts to decrease toxicity of biochemotherapy
by administering subcutaneous outpatient IL-2 did not show a
substantial benefit of biochemotherapy versus chemotherapy
alone.197–199 A meta-analysis demonstrated that although
biochemotherapy seemed to improve overall response rates,
there was no survival benefit for patients with metastatic
melanoma.200
Given the overall poor performance of these agents,
continued basic and translational research is warranted.
Pre-emptive strategies are also being developed. Because a
majority of patients with cutaneous melanoma have some
identifiable risk factor (i.e., sun exposure), chemoprevention
using carotenoids and inhibitors of cyclooxygenase-2 (COX-
2), vascular endothelial growth factor (VEGF) receptor, and
cytochrome P-450 are actively being investigated.201 Outcomes
of this work are much anticipated.
Immunotherapy-immune modulators
Despite many preclinical and clinical studies evaluating
multiple cytokines, vaccines, antibodies, and other types of
immune modulation, alone or in combination with chemo­
therapy, only IL-2 for metastatic disease and interferon alfa for
surgical adjuvant treatment have demonstrated sufficient
success to warrant approval by regulatory authorities.148,189
Nevertheless, there has been continued optimism that immune
modulation can become an effective treatment for patients
with melanoma driven largely by key advances in tumor
immunobiology, including the potential to manipulate and
disrupt immune activation checkpoints and tumor defense
mechanisms; newer approaches to antigen presentation for
immune activation; refinements to procedures for antigen-
specific T-cell expansion; gene transfer to alter lymphocyte
specificity and function; and the potential for discovery of
improved predictive biomarkers to select patients for indi­
vidual treatments.202
Along these lines, Hodi et al. induced autoimmunity in
patients with metastatic melanoma using ipilimumab, an
antibody directed against the cytotoxic T-lymphocyte-associ­
ated antigen CTLA-4.203 CTLA-4 is an immune checkpoint
molecule that down-regulates T-cell activation, and blocking
this molecule is known to promote antitumor immunity.203 In
their multicenter clinical trial, patients with metastatic mela­
noma were randomly assigned to receive either an anti-
CTLA-4 agent (ipilimumab), a vaccine based on a melanoma
antigen, or a combination of the anti-CTLA-4 agent and the
vaccine. An improvement in overall survival, as well as an
improvement in progression-free survival and best overall
response rate, was seen in the patients who received anti-
CTLA-4 therapy, as compared with the patients who received
the vaccine only.203
In addition to CTLA-4, another extensively studied interac­
tion is between programmed death-1 receptor (PD-1) on the
surface of activated T cells with its ligand (PD-L1) on antigen-
presenting cells or tumor cells. PD-1, like CTLA- 4, is expressed
on the surface of activated T cells, and when it binds PD-L1,
the immune response is attenuated. The expression of PD-L1
on tumor cells is thought to play a role in decreased immune
response in the tumor microenvironment, contributing to
tumor growth and spread.
Of note, the side-effect profile of ipilimumab deserves
mention, as 60% of patients suffered adverse events, mostly
immune related. However, this randomized, controlled trial
showed that there was a significant improvement in overall
survival among melanoma patients treated with ipilimumab.
It will likely prove useful in patients with metastatic mela­
noma whose disease progressed while receiving one or more
previous therapies.
Phase I studies of PD-1 and PD-L1 inhibitors have demon­
strated promising results in patients with metastatic mela­
noma.204,205 Randomized controlled trials evaluating survival
benefits for PD-1 and PD-L1 inhibitors are currently being
performed. Like ipilimumab, anti-PD-1/L1 medications have
mostly immune-related adverse events. Early studies have
been reported that are examining the combination of anti-
CTLA-4 and anti-PD-1 medications. Treatment with concur­
rent nivolumab (anti-PD-1 antibody) and ipilimumab results
in higher adverse event rates than administration of the drugs
separately; however, most adverse events were reversible. An
impressive response rate of 40% was seen in patients receiving
the concurrent dosing versus 20% in those treated with a
sequenced regimen.206 A subsequent update on this trial
demonstrated an 82% survival rate at 1 year for the concurrent
regimen and a 75% survival rate at 2 years.207 These results
show improved response rates with the combination of mul­
tiple immunotherapy agents, and suggest that patients who
experience disease progression on one agent may still benefit
from the alternate agent. Given the results of these studies, as
well as additional trials, nivolumab was approved by the FDA
in December 2014 for the treatment of advanced melanoma
after the failure of other treatments.208

593
Summary
Table 29.11  Surveillance guidelines
Office visits and physical examination
Stage 0
Yearly by dermatologist or
primary care physician
Stage I
Every 6 months for 5 years
Stage II–IV
Every 3 months for 2 years
Every 6 months for 3 years
Metastatic surveillance
Lactate dehydrogenase
At each visit, at least yearly
  level and complete
  blood cell count
Chest radiograph
Every other visit, at least yearly
CT scan ± PET
With laboratory test or chest
radiograph abnormality,
physical findings, or symptoms
Table 29.12  Protocol for follow-up surveillance
Physical examination
Chest radiography
Liver function tests
Imaging
Stage I, T1
Semiannual × 2 yr, then annually
–
–
Stage I–II, T2–4
Every 3 months × 3 yr, then
semiannually
Annual
Annual
Stage III (lymph
nodes positive)
Every 3 months × 3 yr, then
semiannually
Annual
Annual
Annual or as
indicated
serology, and chest X-ray, which will detect most recurrences.
Routine screening with CT of the head, chest, and abdomen
is not recommended, unless clinical suspicion for metastases
is high. Chest X-rays and liver serology, despite a relatively
low yield,217 are inexpensive and useful for establishment of
baseline values. The utility of PET or PET-CT imaging for the
surveillance of affected patients is still under investigation.
Additionally, the prospect of using specific serum screening
tools such as tyrosinase mRNA detected by RT-PCR is both
clinically exciting and ethically challenging.218
The National Cancer Institute recommends that most
patients without a family history and no atypical nevi should
have follow-up evaluations every 6 months for the first 2
years. Thereafter, yearly follow-up is appropriate. Those with
a family history or atypical nevi are followed up every 3
months.216
Summary
Melanoma remains a challenging and important clinical
problem, with a rapidly rising yearly incidence. Wide local
excision remains the primary treatment modality for primary
disease. Sentinel lymph node biopsy is indicated for patients
with clinically negative nodes and primary lesions with
aggressive features, generally, thickness greater than 1 mm. If
the SLN is positive, completion lymphadenectomy is indi­
cated for control of regional disease. Unfortunately, the overall
cure rates for advanced melanoma have not significantly
improved during the past several decades because we are
unable to treat the subclinical micrometastases that are present
Molecularly-targeted treatment of
metastatic melanoma
Molecularly-targeted chemotherapy for metastatic melanoma
has changed dramatically since 2010, with the advent of small
inhibitor therapies, especially for melanomas with BRAF
mutations. It was demonstrated in 2002 that approximately
50% of human melanomas harbor an activating mutation in
BRAF, an upstream component of the mitogen-activated
protein (MAP) kinase pathway; the mutation is a substitution
of glutamic acid for valine (the V600E mutation).209 Melanoma
cells containing the BRAF mutation are dependent on MAP
kinase signaling for their growth and survival.210 These find­
ings suggested the possibility that melanoma may be amenable
to targeted therapy.
There are three FDA-approved MAP kinase inhibitors
used for the treatment of malignant melanoma: 2 BRAF
inhibitors (BRAFi), vemurafenib and dabrafenib, and the first-
in-class MEK inhibitor (MEKi), trametinib. Their approval
was based on randomized, phase III trials in which each
of the investigational agents was compared against dacarba­
zine for patients with unresectable BRAFV600E(K)-mutant
MM.211–213 Responses were seen early during treatment, most
responses were partial, and the development of secondary
resistance was seen in the majority of patients.214
It seems clear that melanomas can be categorized by specific
molecular changes that drive their proliferation;215 targeting
the activated pathways in individual tumors may lead to tumor
regression and possible cure. This type of personalized cancer
therapy will likely play a prominent role in the care of patients
with melanoma and other cancers in the coming decade.
Surveillance
Patients treated at the Yale Melanoma Unit are initially moni­
tored closely (Table 29.11), with increasing intervals each
year. The importance of dermatologic evaluation, photo
documentation, and close follow-up cannot be overstated.
Education of the patient for early self-detection of recur­
rences together with interval physician follow-up has been
most successful in maintaining an effective monitoring
program.216 Patients are examined for local or in-transit
metastases at varying intervals based on the stage of the
melanoma at diagnosis (Table 29.12).
Tumor recurrences correlate with the thickness of the
lesion. Between 60% and 70% of recurrences appear in the first
18 to 24 months after surgical treatment (see Table 29.8).165 The
earliest recurrences are to local or regional lymph nodes, fol­
lowed by in-transit metastases; distant metastases appear last.
Screening is typically by physical examination, liver-function

594
CHAPTER 29 • Melanoma
in systemic organs at the time of the treatment of the primary
melanoma. Once these metastases become evident clinically,
there is little chance of cure by further surgery, chemotherapy,
radiation therapy, or combinations of these treatment modali­
ties. Adjuvant trials with chemotherapy and biochemotherapy
have not demonstrated uniform success for any meaningful
period of time. Therefore, we cannot overemphasize the
importance of clinical trials, and patients with advanced
melanoma should be encouraged to enroll in clinical trials
testing different adjuvant strategies whenever possible. Recent
successes in controlling metastatic lesions with molecularly-
targeted treatments hold promise for personalized treatments
for genetic mutations in the future.
Bonus images for this chapter can be found online at

Fig. 29.1 Autopsy findings of patient with melanoma of right ankle spreading in
a centripetal manner to right groin and remainder of body while sparing the left
leg. (Redrawn from Handley WS. The pathology of melanotic growths in relation
to their operative treatment. Lecture I. Lancet. 1907;1:927.)
Fig. 29.2 Handley recommended removal of melanoma (a) together with 1 inch
(f) of skin (b) and 2 inches (g) of underlying subcutaneous fat (c), muscle
fascia (d), and muscle (e). h, skin incision. (Redrawn from Handley WS. The
pathology of melanotic growths in relation to their operative treatment. Lecture I.
Lancet. 1907;1:927.)
46. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma of the
Skin. AJCC Cancer Staging Manual. 8th ed. Springer; 2017:
563–585. The most recent melanoma staging recommendations were
made on the basis of a multivariate analysis of 30 946 patients with
stages I–III melanoma and 7972 patients with stage IV melanoma. For
patients with localized melanoma, tumor thickness, mitotic rate, and
ulceration are the most dominant prognostic factors. For patients with
regional metastases, components that define the N category are the
number of metastatic nodes, tumor burden, and ulceration of the primary
melanoma. All patients with microscopic nodal metastases, regardless of
extent of tumor burden, are classified as stage III. For patients with
distant metastases, the two dominant components defining the M
category continue to be the site of distant metastases and serum lactate
dehydrogenase level.
61. Breslow A. Thickness, cross-sectional areas and depth of invasion
in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:902–
908. Alexander Breslow first decribed the use of an ocular micrometer to
measure the maximal thickness of melanomas, and demonstrated a
correlation of depth of invasion with patient outcome.
63. Morton DL, Wen DR, Wong JH, et al. Technical details of
intraoperative lymphatic mapping for early stage melanoma. Arch
Surg. 1992;127:392–399. Morton et al. first described the use of sentinel
lymph node biopsy in the treatment of melanoma. This technique
identifies, with a high degree of accuracy, patients with early-stage
melanoma who have nodal metastases and are likely to benefit from
radical lymphadenectomy.
85. Morton DL, Hoon DS, Cochran AJ, et al. Lymphatic mapping and
sentinel lymphadenectomy for early-stage melanoma: therapeutic
utility and implications of nodal microanatomy and molecular
staging for improving the accuracy of detection of nodal
micrometastases. Ann Surg. 2003;238:538–549, discussion 49–50.
112. Sladden MJ, Balch C, Barzilai DA, et al. Surgical excision margins
for primary cutaneous melanoma. Cochrane Database Syst Rev.
2009;(4):CD004835. This systematic review summarizes the evidence
regarding width of excision margins for primary cutaneous melanoma.
Of the five randomized controlled trials, there was no statistically
significant difference in overall survival between narrow (1–2 cm) or
wide (3–5 cm) excision margins. Based on the individual trials and
meta-analysis, current randomized trial evidence is insufficient
to address optimal excision margins for primary cutaneous
melanoma.
116. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary
cutaneous malignant melanoma. Comparison of excision with
margins of 1 or 3 cm. N Engl J Med. 1988;318:1159–1162.
123. Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in
high-risk malignant melanoma. N Engl J Med. 2004;350:757–766.
148. Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of
eastern cooperative oncology group and intergroup trials of
adjuvant high-dose interferon for melanoma. Clin Cancer Res.
2004;10:1670–1677.
152. Barranco SC, Romsdahl MM, Humphrey RM. The radiation
response of human malignant melanoma cells grown in vitro.
Cancer Res. 1971;31:830–833.
203. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with
ipilimumab in patients with metastatic melanoma. N Engl J Med.
2010;363:711–723. In this study, ipilimumab, which potentiates an
antitumor T-cell response, demonstrated improvement in overall survial
(10.0 months vs. 6.4 months) in patients with unresectable stage III or
IV melanoma. Adverse events can be severe, long-lasting, or both, but
most are reversible with appropriate treatment.
214. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated,
activated BRAF in metastatic melanoma. N Engl J Med.
2010;363:809–819. The authors conducted a multicenter, phase I, dose
escalation trial of PLX4032, an orally available inhibitor of mutated
BRAF, followed by an extension phase involving the maximum dose that
could be administered without adverse effects. Patients received PLX4032
twice daily until they had disease progression. BRAF (v-raf murine
sarcoma viral oncogene homolog B1) is a signal transduction molecule
that has an activating mutation (glutamic acid for valine at amino acid
600; V600E) in half of all melanomas. In the dose escalation cohort,
among the 16 patients with melanoma whose tumors carried the V600E
BRAF mutation and who were receiving 240 mg or more of PLX4032
twice daily, 10 had a partial response and 1 had a complete response.
Among the 32 patients in the extension cohort, 24 had a partial response
and 2 had a complete response. The estimated median progression-free
survival among all patients was more than 7 months. Treatment with
PLX4032 in the majority of patients with tumors that carry the V600E
BRAF mutation resulted in complete or partial tumor regression.
Access the complete reference list online at

594.e1
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185. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy:
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187. Besser MJ, Shapira-Frommer R, Treves AJ, et al. Clinical responses
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189. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant
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193. Legha SS, Ring S, Eton O, et al. Development of a
biochemotherapy regimen with concurrent administration of
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194. O’Day SJ, Boasberg PD, Piro L, et al. Maintenance biotherapy for
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195. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy
versus chemotherapy for metastatic melanoma: results from a
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196. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing
concurrent biochemotherapy with cisplatin, vinblastine,
dacarbazine, interleukin-2, and interferon alfa-2b with
cisplatin, vinblastine, and dacarbazine alone in patients
with metastatic malignant melanoma (E3695): a trial
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197. Ridolfi R, Chiarion-Sileni V, Guida M, et al. Cisplatin, dacarbazine
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198. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin, and
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Group. J Clin Oncol. 2005;23:6747–6755.
199. Bajetta E, Del Vecchio M, Nova P, et al. Multicenter phase III
randomized trial of polychemotherapy (CVD regimen) versus the
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200. Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy
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201. Demierre MF, Nathanson L. Chemoprevention of melanoma: an
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202. Sznol M. Betting on immunotherapy for melanoma. Curr Oncol
Rep. 2009;11:397–404.
203. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with
ipilimumab in patients with metastatic melanoma. N Engl J Med.
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antitumor T-cell response, demonstrated improvement in overall survial
(10.0 months vs. 6.4 months) in patients with unresectable stage III or
IV melanoma. Adverse events can be severe, long-lasting, or both, but
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204. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of
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206. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus
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207. Sznol M, Kluger HM, Callahan MK, et al. Survival, response
duration, and activity by BRAF mutation status of nivolumab
(NIVO, anti-PD-1, BMS-936558, ONO- 4538) and ipilimumab
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208. Green J, Ariyan C. Update on immunotherapy in melanoma. Surg
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210. Wellbrock C, Karasarides M, Marais R. The RAF proteins take
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594.e6
CHAPTER 29 • Melanoma
211. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of
vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive
melanoma (BRIM-3): extended follow-up of a phase 3,
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212. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-
mutated metastatic melanoma: a multicentre, open-label, phase 3
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MEK inhibition in BRAF-mutated melanoma. N Engl J Med.
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214. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated,
activated BRAF in metastatic melanoma. N Engl J Med.
2010;363:809–819. The authors conducted a multicenter, phase I, dose
escalation trial of PLX4032, an orally available inhibitor of mutated
BRAF, followed by an extension phase involving the maximum dose that
could be administered without adverse effects. Patients received PLX4032
twice daily until they had disease progression. BRAF (v-raf murine
sarcoma viral oncogene homolog B1) is a signal transduction molecule
that has an activating mutation (glutamic acid for valine at amino acid
600; V600E) in half of all melanomas. In the dose escalation cohort,
among the 16 patients with melanoma whose tumors carried the V600E
BRAF mutation and who were receiving 240 mg or more of PLX4032
twice daily, 10 had a partial response and 1 had a complete response.
Among the 32 patients in the extension cohort, 24 had a partial response
and 2 had a complete response. The estimated median progression-free
survival among all patients was more than 7 months. Treatment with
PLX4032 in the majority of patients with tumors that carry the V600E
BRAF mutation resulted in complete or partial tumor regression.
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218. Mellado B, Del Carmen Vela M, Colomer D, et al. Tyrosinase
mRNA in blood of patients with melanoma treated with adjuvant
interferon. J Clin Oncol. 2002;20:4032–4039.

30 
Implants and biomaterials
Timothy W. King and Charles E. Butler
SYNOPSIS
■ What is a biomaterial? In order to discuss biomaterials, we must first
define this term.
■ There are many definitions of biomaterials but a widely used one from
the National Institutes of Health defines a biomaterial as “any
substance (other than a drug) or combination of substances synthetic
or natural in origin, which can be used for any period of time, as a
whole or part of a system which treats, augments, or replaces tissue,
organ, or function of the body”.1
■ With the advent of tissue engineering and regenerative medicine in
recent years, the definition has broadened to include “any material
used in a medical device intended to interact with biological systems”,
allowing for structures and combination devices that actively interact
with the body to be included in the field.2
■ Biomaterials can be synthetic (i.e., those made by humans) or
biological (i.e., those produced by a biological system).
■ Further classifications based on development stage or material
characteristics are also common but are beyond the scope of this
chapter.
Access the Historical Perspective section and Box 30.1
online at

For the purpose of this chapter, biomaterials will be divided
into the following general categories: metals, polymers,
ceramics, glues, skin substitutes, and bioprosthetics.
Metals
In order to achieve the mechanical and biophysical properties
desired for applications in medicine, combinations of metals,
called alloys, have been developed. These alloys are designed
to be inert and withstand the corrosive environment found
within the human body. In general, these alloys have mechani­
cal properties that exceed the properties of the natural tissue
they are supporting because, unlike natural tissues, they are
unable to recover from deformation.
Stainless steel
Stainless steel has been used as a biological implant since the
1920s.6 Stainless steel was designed to prevent corrosion and
consists of over 10 individual compounds which provide it
with the desired chemical and mechanical properties. The
stainless steels used in medical applications are iron-
chromium-nickel alloys with at least 17% chromium (Table
30.1). The chromium creates a protective surface, which con­
tributes to the alloy’s anticorrosive properties. The most
commonly used stainless steel alloy in medical applications is
“316L” which, in addition to the chromium composition, has
a low carbon content to prevent carbide formation, and a high
nickel content to increase the strength and hardness of the
alloy. Stainless steel has a relatively high tensile strength but
is easily deformed (bent). While this is useful in some applica­
tions, such as the application of arch bars for maxillomandibu­
lar fixation, overall these mechanical properties are less
desirable than other currently available materials such as
cobalt-chromium and titanium. In addition, stainless steel can
leach metallic ions into the surrounding tissues, causing a
severe inflammatory reaction and pain, which may require
surgical removal of the implants in some patients. Stainless
steel is currently used in surgical wire and in arch bars. His­
torically rigid fixation systems utilized stainless steel but
other alloys have replaced stainless steel in this application.
Cobalt-chromium
Historically, cobalt-chromium alloys have been one of the
most significant biomaterials used in humans. Vitallium, a
cobalt-chromium-molybdenum (Co-Cr-Mo) alloy (ASTM 75),
was first described in 1932 to address some of the problems
experienced with stainless steel. These alloys replace the iron

595.e1
Historical perspective
Historical perspective
The development of biomaterials has exploded over the past
50 years. In fact, prior to World War II, the term “biomaterials”
did not exist. Although there have been reports of biomateri­
als being used, in the form of sutures, 32 000 years ago,2,3 the
vast majority of biomaterials have been developed in the last
60 years. The modern era of medical implants might be attrib­
uted to a British ophthalmologist, Harold Ridley, in the late
1940s. He noticed that shards of canopy plastic that had been
unintentionally implanted in the eyes of Spitfire fighter pilots
who had been shot at by enemy machine guns seemed to heal
without any adverse reaction. He concluded that the plastic
used to make the Spitfire canopy, poly(methyl-methacrylate),
might be used to make implant lenses for patients with cata­
racts. In 1949 he implanted the first artificial lens into a human.
This observation and innovation were the precursors to the
modern intraocular lenses that are now used over 10 million
times per year for patients with cataracts.2
Around the same time, several independent groups of
surgeons and engineers developed biomaterial-based implants
such as vascular grafts, hip replacements, and heart valves.
These innovators defined the foundations of biomaterial
science in an era before principles for medical materials
were established. By the 1950s, as surgeons, engineers, and
scientists continued to create these new implant materials, it
BOX 30.1  Properties of an ideal implant
Minimal foreign-body reaction
Elastic or supple
Can be tailored easily
Good tissue incorporation
Allows collagen ingrowth
Promotes permanent tissue repair
Good tensile strength
Tolerates infected environment
Minimal wound complications
(Modified from Cumberland VH. A preliminary report on the use of prefabricated
nylon weave in the repair of ventral hernia. Med J Aust. 1952;1:143–144; and
Scales JT. Materials for hernia repair. Proc R Soc Med. 1953;46:647–652.)
became clear that there were certain properties that an ideal
implant would impart. Cumberland4 and Scales5 described
the properties of an ideal implant (Box 30.1).
Remarkably, although these criteria were published about
60 years ago, they are still the fundamental properties that all
modern biomaterials attempt to achieve.

596
CHAPTER 30 • Implants and biomaterials
with cobalt (~60% of the composition), increase the chromium
to 25–30% for additional corrosion resistance, and contain
5–7% molybdenum for additional strength (see Table 30.1).
Co-Cr-Mo alloy was used in some of the early craniofacial
miniplates and screws and helped to revolutionize that field.
The major disadvantage of Co-Cr-Mo alloys is the scatter
artifact on computed tomography (CT) imaging. Because of
this, and several other benefits, titanium has essentially
replaced Co-Cr-Mo alloys in most biomedical applications.7
However, it is still used in dental applications.
Titanium
Titanium alloys were introduced into medical applications in
the early 1980s.6,8 Since that time titanium has almost entirely
replaced the other alloys in medical applications. This is
because the titanium alloys are stronger, lighter, have higher
resistance to corrosion, and generally cause less inflammation.
Titanium also has less stress shielding (localized osteopenia
secondary to the implant protecting the bone from normal
loading) than other metal implants because they have less
stiffness. Titanium alloys have less than 0.5% iron in them (see
Table 30.1), which provides them with two additional benefi­
cial properties: they do not set off metal detectors, and they
do not create a significant artifact on CT or magnetic resonance
imaging studies. Finally, titanium can form chemical bonds
with the surrounding mineralized bone without the typical
fibrous tissue forming between the implant and bone. This
unique characteristic allows titanium to be used to create
osteointegrated implants. In many cases pure titanium rather
Table 30.1  Composition of common metal alloys
Element
Stainless steel (ASTM F138)*
Co-Cr (ASTM F90)†
Titanium (ASTM F136)‡
Weight %
Weight %
Weight %
Chromium
16–18
27–30
–
Nickel
10–14
2.5 max
–
Molybdenum
2–3
5–7
–
Carbon
0.03 max
0.35 max
0.08 max
Iron
Balance
0.75 max
0.25 max
Manganese
2.00 max
1.00 max
–
Phosphorus
0.045 max
–
–
Sulfur
0.03 max
–
–
Silicon
1.00 max
1.00 max
–
Nitrogen
0.10 max
–
–
Cobalt
–
Balance
–
Oxygen
–
–
0.013 max
Aluminum
–
–
5.5–6.5
Vanadium
–
–
3.5–4.5
Titanium
–
–
Balance
*ASTM. Standard specification for wrought 18chromium-14nickel-2.5molybdenum stainless steel bar and wire for surgical implants (UNS S31673). West Conshohocken,
PA: ASTM International; 2008.
†ASTM. Standard specification for wrought cobalt-20chromium-15tungsten-10nickel alloy for surgical implant applications (UNS R30605). West Conshohocken, PA: ASTM
International; 2009.
‡ASTM. Standard specification for wrought titanium-6 aluminum-4 vanadium ELI (extra low interstitial) alloy for surgical implant applications (UNS R56401). West
Conshohocken, PA: ASTM International; 2008.
(Adapted from Holmes RE. Alloplastic materials. In: McCarthy JG, ed. Plastic Surgery. New York: WB Saunders; 1990:698–731.)
than an alloy is used for medical implants. Plastic surgery
applications of titanium include plates and screws for rigid
fixation of bone and mesh for use in applications such as
orbital wall reconstruction (Fig. 30.1).
Gold
Although gold is chemically inert, in its pure form it has poor
mechanical properties. Thus, when some strength is needed
(for example, in dental fillings), a gold alloy is used. For
applications such as eyelid weights in patients with lagoph­
thalmos,9 where strength is less of an issue, 24-carat gold alloy
(99.9% w/w purity) is commonly used to insure chemical
inertness.
Platinum
Like gold, platinum is an inert metal and is the material of
choice for patients with gold sensitivity who are in need of an
eyelid implant for lagophthalmos. Platinum is denser than
gold, thus the eyelid implants have a lower profile and are
less noticeable than gold implants.
Some formulations containing platinum have been shown
to be immunogenic and thus have raised concerns over long-
term exposure. Because the Centers for Disease Control state
that short-term exposure to platinum salts may cause irrita­
tion of the eyes, nose, and throat and long-term exposure may
cause both respiratory and skin allergies, the current Occupa­
tional Safety and Health Administration standard for soluble
platinum salts is 2 mcg/m3 of air averaged over 8 hours.

597
Polymers
polymer chains are cross-linked, the ability for them to move
independently is decreased. For example, a polymer with
freely flowing chains might exist as a liquid and, as the
amount of cross-linking is increased, it can become a “gel” or
“solid”.
Silicone
Silicone is probably the most maligned and misunderstood
biomaterial used in medicine today. This is likely due to the
controversy revolving around the use of silicone in breast
implants. Silicone gel-filled breast implants were first intro­
duced in the US in 1962 and consisted of two shells made of
thick, smooth-walled silicone elastomer, filled with a viscous
silicone gel material (dimethylsiloxane) and glued together.
Multiple variations and modifications to the shell and gel
were made over the years in an attempt to improve the out­
comes of breast augmentation and reduce the associated
complications. In 1988, the US Food and Drug Administration
(FDA), out of concerns from reports of implant failure and
allegations of resultant complications and illness, relabeled
breast implants as class III medical devices, and called for data
from manufacturers showing the safety and effectiveness of
these devices.13,14
Platinum is also used as a catalyst in the formation of some
polymers. Platinum black, a fine powder (1 nm–1 µm) form
of platinum, is used in many of these reactions.10 Platinum
black catalyzes the addition of hydrogen to unsaturated
organic compounds and is used in the production of silicone
gel breast implants (see below).
Platinum complexes have also been used as chemotherapy
and show good activity against some tumors. Cisplatin, the
best-known platinum chemotherapeutic agent, has activity
against multiple types of cancer. However, it has some signifi­
cant side effects, including cumulative irreversible kidney
damage and deafness.11,12
Polymers
Polymers are molecules composed of repeating subunits.
They are typically defined as a backbone series of molecules
with side chains that are covalently bound to the backbone
molecules. The physical properties of the polymer are defined
by the structure of the monomer, the number of monomer
units in the polymer chain, and the degree of cross-linking
(the amount of bonding between two polymer chains). As
Fig. 30.1  Titanium plates for midface reconstruction. (A) Various 2.0-mm plates
and screws. The screws are 7, 5, and 3 mm in length (left to right). (B) Four-hole
plates and screws for the 1.0-, 1.5-, 2.0-, and 2.3-mm plating systems. (C) A 1.0-,
1.5-, and 2.0-mm “L” plate. The screws are all 5 mm in length. Note that, by
convention, the size of the plates is based upon the screw diameter.
A
B
C

598
CHAPTER 30 • Implants and biomaterials
In 1992, the FDA claimed that there was “inadequate
information to demonstrate that breast implants were safe
and effective” and placed a moratorium on silicone gel breast
implants for cosmetic purposes but allowed their continued
use for reconstruction after mastectomy, correction of con­
genital deformities, or replacement of ruptured silicone gel-
filled implants due to medical or surgical reasons. In order to
address this concern, the Department of Health and Human
Services appointed the Institute of Medicine of the National
Academy of Science (IOM) to begin one of the most extensive
research studies in medical history. Their charge was to
examine potential complications during or after silicone-based
breast implant surgeries. In 1999, after reviewing years of
evidence and research concerning silicone gel-filled breast
implants, the IOM released a comprehensive report on both
saline-filled and silicone gel-filled breast implants entitled
Safety of Silicone Breast Implants.15 The IOM found that “evi­
dence suggests diseases or conditions such as connective
tissue diseases, cancer, neurological diseases or other systemic
complaints or conditions are no more common in women
with breast implants than in women without implants”. Most
individual studies and all systematic review studies have also
subsequently failed to find a link between silicone breast
implants and disease.13,14
In 2006, the ban imposed by the FDA was lifted and restric­
tions on the use of silicone gel-filled breast implants produced
by the two manufacturers for breast reconstruction and for
cosmetic breast augmentation ended. The FDA approval
required a complete 10-year study on women who have
already received the implants and a 10-year study on the
safety of the devices in 40 000 women. It was also mandated
that patients be given brochures explaining the risks.13,14
So what is silicone? It is important to understand this ques­
tion in light of the history of breast implants. Silicone is a
family of polymers consisting of alternating silicon (Si) and
oxygen (O) molecules. Table 30.2 shows the nomenclature of
silicone. Siloxane, the basic repeating unit of silicone, consists
of silicon, oxygen, and a saturated hydrocarbon (alkane) side
group. Poly-dimethylsiloxane (PDMS) |(CH3)2SiO|n is the
polymer used in most medical applications. PDMS is a very
pure polymer that consists of the silicone backbone (silicon
and oxygen) with two methyl side chains. It is one of the most
inert biomaterials available for use in medical devices. Alter­
ing the length and molecular weight of the PDMS changes the
mechanical properties and behavior of the silicone gel. PDMS
molecules with less than 30 monomers are defined as low-
molecular-weight formulations and have a viscosity similar
to baby oil. High-molecular-weight formulations contain
more than 3000 monomers and are solids. Controlling the
degree of cross-linking, changing additives, and adjusting the
curing process can also modify the mechanical properties of
silicone. For example, the silicone gel found in breast implants
is cured in a hydrosilation reaction where some of the methyl
side chains (CH3) are replaced by vinyl side chains (CH=CH2)
that then allow the silicone chains to cross-link with each
other. This reaction is catalyzed by platinum and some residual
platinum can be found in silicone gel breast implants. The
silicone shell on breast implants is made of fully polymerized
silicone with an amorphous (noncrystalline) silica filler added
for strength (Fig. 30.2).
Other plastic surgery applications of silicone include
facial implants for malar, nasal, and chin reconstruction or
Table 30.2  Silicone nomenclature
Term
Chemical
formula
Description
Silicon
Si
Most abundant element on
earth
Does not occur naturally in
its metallic state
Silica
SiO2
Sand, marble, or quartz
Silicate
Na2SiO3
In one form, used as a
desiccant (e.g., in
anesthesia machines)
Siloxane
R2SiO
Monomer of silicon and
oxygen
Silicone
|R2SiO|n
Polymers of silicon and
oxygen
Poly-
dimethylsiloxane
|(CH3)2SiO|n
The building block for most
medical-grade silicone
products, including breast
implants
(Adapted from Miller MJ, Ogunleye OT. Biomaterials. In: Guyuron B, Eriksson E,
Persing JA, et al., eds. Plastic Surgery Indications and Practice. New York:
Saunders Elsevier; 2009:57–66.)
Fig. 30.2  A silicone gel-filled breast implant (Mentor).
augmentation, and orbital floor reconstruction. Hand sur­
geons use silicone implants for arthroplasty, flexor tendon
replacement, and bone block spacers. Silicone is beneficial in
these applications because it is relatively inert, malleable, and
deformable. Low-molecular-weight silicone was used in the
past as an injectable soft-tissue filler. However, severe tissue
reaction and migration of the silicone have led many physi­
cians to avoid this application.
Silicone is probably the most studied implantable material
available today. After over 35 well-conducted studies from
many countries, there is no conclusive evidence that this
material causes disease. Furthermore, medical-grade silicone
is ubiquitous, being found in more than 1000 medical products
as either a component or as a residuum from the manufactur­
ing process. For example, every disposable needle and syringe,

599
Polymers
significant limitations of ePTFE mesh used for hernia repair,
including infection often requiring explantation and limited
incorporation strength to the surrounding fascial edge com­
pound to macroporous meshes such as polypropylene.
Polyester
Polyester contains an ester functional group in its main chain.
Mersilene is a polyester fiber mesh knitted product for use in
herniorrhaphy. Polyester mesh is softer and more hydrophilic
than polypropylene, and in animal studies has shown better
tissue ingrowth. Dacron is another form of polyester that has
been used for vascular grafts.
Polyprolene
Polyprolene, or polypropylene, has a carbon backbone and
side chains of hydrogen and methyl groups. It has been used
in hernia and pelvic organ prolapse repair and is rarely
rejected. However, polypropylene mesh can erode through
the soft tissues over time. Therefore, the FDA has issued warn­
ings on the use of polypropylene mesh in pelvic organ pro­
lapse, specifically when in close proximity to the vaginal wall
secondary to the number of mesh erosions reported by patients
over the past few years.28 It is also used as suture material
because of its strength and low foreign-body reaction within
the body. Knitted polypropylene surgical meshes are com­
monly used for hernia repair owing to a high ultimate tensile
strength of the mesh and strong fibrovascular incorporation
into the fascial defect edge. Direct placement over abdominal
viscera can cause dense adhesions, fistula, and erosion. Reop­
eration through a polypropylene mesh hernia repair is often
challenging due to this generalized fibrotic scarring to adja­
cent intraperitoneal viscera.
Polyethylene
Polyethylene consists of a carbon backbone with hydrogen
side chains (ethylene). A high-density porous form of poly­
ethylene (Medpor) is used for facial implants (Fig. 30.3). The
as well as intravenous tubing, is lubricated with silicone.
Medications in stoppered vials contain residual silicone
from its use in the manufacturing process. Silicone elastomers,
in their solid form, are used for pacemaker coatings,
tubing, prosthetic joints, hydrocephalus shunts, and various
facial and penile implants. Like breast implants, some testicu­
lar and chin implants are made of a silicone gel in a silicone
envelope.
Silicones are also found in some medications. If a medica­
tion contains an ingredient with the name “methicone” (e.g.,
simethicone), this is a silicone that has been modified for
human consumption. Silicones are also used in household
items such as lipstick, suntan/hand lotion, hairspray, pro­
cessed foods, and chewing gum. Medical-grade silicones
invoke a nonspecific foreign-body response, resulting in
typical macrophage invasion, giant cell formation, and even­
tual scarring.16
Extensive investigations by several prestigious scientific
bodies (e.g., the IOM,17,18 and the UK Department of Health19)
have failed to show that systemic illness is definitively attrib­
uted to silicones. However, in January of 2011, the FDA,
based upon a series of case reports which followed the sen­
tinel case reported in 1997,20 issued a safety communication
stating, “women with breast implants may have a very small
but increased risk of developing anaplastic large cell lym­
phoma (ALCL) in the scar capsule adjacent to the implant”.21,22
At the time of the communication, the FDA was aware
of approximately 60 cases of breast implant patients who
had developed ALCL out of the approximately 5–10 million
women who had received breast implants worldwide. Since
then over 200 women worldwide have been diagnosed with
breast implant-associated ALCL (BI-ALCL). The exact cause
and mechanism of BI-ALCL is unknown but is not limited to
women with silicone-filled implants as women with saline
filled implants have also developed the disease.23,24 For more
details about BI-ALCL the reader is referred to Volume 5,
Chapter 12.
The next progression in silicone gel breast implants was the
approval by the FDA of cohesive gel implants (commonly
referred to as “gummy-bear” implants). All three breast
implant manufacturing companies have received approval for
their cohesive gel implants, Sientra (Santa Barbara, CA) in
March 2012; Allergan (Irvine, CA) in February 2013; and
Mentor (Irvine, CA) in June 2013.25
Polytetrafluoroethylene
Polytetrafluoroethylene (PTFE), also known as Teflon, was
accidentally invented by Roy Plunkett in 1938 while he was
trying to develop a refrigerant.26 It consists of a carbon back­
bone with fluorine side chains. Expanded PTFE (ePTFE or
Gore-Tex) was created by Bob Gore in 1969 when he rapidly
stretched PTFE. It is very stable chemically, cannot be cross-
linked (which makes it flexible), and has a nonadherent
surface. When made with a pore size of 10–30 µm it will allow
some limited tissue ingrowth. It has been used for a wide
variety of applications, from hiking boots to coatings on
frying pans. Within the medical field it is used for vascular
grafts, mesh for abdominal wall reconstruction, and implants
for facial augmentation.27 The nonadhesive properties of
ePTFE have been employed in surgical meshes used for hernia
repair to reduce repair site adhesion. However, there are
Fig. 30.3  Medpor (high-density porous form of polyethylene) implants used in
facial augmentation.

600
CHAPTER 30 • Implants and biomaterials
Ceramics
People have been using ceramic materials for thousands of
years. However, medical applications of ceramics were not
developed until the 1960s. Of the many ceramics available,
only a few have been found to be suitable for implantation in
humans. Ceramics have a crystalline structure and are made
up of inorganic, nonmetallic molecules whose individual
electrons are strongly bound to each individual atom (called
heteropolar bonding; in contrast, homopolar bonding, seen in
metals, allows the electrons to flow freely between atoms).
The manufacturing of ceramic materials is achieved through
a process called sintering, which requires the material to be
fused together under high pressure and temperature. Ceram­
ics have appealing physical properties for biomedical use,
including decreased foreign-body response, resisting bacterial
colonization, a high compressive strength, and tissue ingrowth
into porous materials (100 µm pore size for bone and 30 µm
pore size for soft tissue). However, their benefits are overshad­
owed by their weaknesses; namely they are brittle and fracture
easily under tensile, torsional, or bending loads. Their
main uses in plastic surgery are for bone augmentation and
replacement.
Calcium phosphates are the most common ceramics used
in plastic surgery. In addition, calcium phosphates have been
shown in the laboratory to be both osteoinductive and osteo­
conductive, but this has not been demonstrated in the clinical
setting.
Calcium phosphates come in two formulations for medical
use: hydroxyapatite (Ca10(PO4)6(OH)2) and tricalcium phos­
phate (Ca3(PO4)2). Tricalcium phosphate has a faster rate of
resorption and replacement by bone when compared to
hydroxyapatite. They are available as granules for injection,
blocks, both solid and porous, and the hydroxyapatite is also
available as a cement paste. These implants are commonly
used to reconstruct nonload-bearing bones of the face and
cranium. The cement paste is beneficial in select cases, such
as cranioplasty, because it is malleable and can be molded
during the case.
Adhesives and glues
The first fibrin tissue adhesive was described in 1944 and was
used to aid in the adherence of skin grafts to the recipient
tissue bed. The first commercially manufactured fibrin sealant
became available in 1978. Cyanoacrylate was synthesized in
1949 but this early product created a severe foreign-body
reaction. Through chemical modifications to molecule, engi­
neers were able to decrease the foreign-body reaction and
create a clinically relevant product. There are several tissue
adhesives available for clinical use. Most commonly, these
adhesives are used to seal two tissues together or to provide
hemostasis. Many of the adhesives possess both properties.
Ideally, tissue adhesives should possess five characteristics
(Box 30.2). Several classes of tissue adhesive are available and
each will be discussed in the next sections.30
Platelet gels
Platelet gels are derived from platelet-rich plasma (PRP). The
starting material is 70 mL of whole blood that undergoes
porosity allows for tissue and vascular ingrowth. It can also
be carved to customize the implant for individual patients.
The implants are firmer and stiffer than the ePTFE implants
and, because of the size of the pores, are more difficult to place
because the soft tissues adhere to it more readily. In addition,
the soft-tissue ingrowth makes the implant more difficult to
remove. Porous polyethylene alone or with titanium mesh
embedded within it is available for reconstruction of the
orbital floor. One of the disadvantages of the polyethylene
alone for orbital floor reconstruction is that the implant does
not show up well on CT, making it difficult to diagnose a
malpositioned implant.
Biodegradable polymers
Biodegradable polymers were developed to try to overcome
some of the disadvantages associated with permanent
implants. Most biodegradation begins through a chemical
reaction such as hydrolysis or oxidation and involves some
sort of biological process (e.g., enzymatic or cellular process)
to eliminate the material completely. In addition to the
requirement that the material itself must be biocompatible, all
of the breakdown products of the material must be biocom­
patible as well.29
Although there are a multitude of materials that will
degrade in vivo, there are only a few that are clinically relevant
as biodegradable polymers. Most of these are α-hydroxy
acids, specifically poly(lactic acid) (PLA), poly(glycolic acid)
(PGA) and combinations, or copolymers, of these individual
polymers know as poly(lactic-co-glycolic acid) (PLGA). These
polymers degrade through hydrolysis, ending in lactic or
glycolic acid, a common byproduct of normal biochemical
pathways.
Most surgeons are familiar with this polymer as it is
the polymer used to make Vicryl (polyglactin 910;
Ethicon, Somerville, NJ). These polymers have also been used
to create biodegradable mesh for use in abdominal wall
reconstruction and plating systems for craniofacial or hand
applications.
Altering the ratios of lactic to glycolic acid or adding
carbon fibers or other polymers can modify the rate of deg­
radation. In general, increasing the concentration of lactic
acid decreases the rate of degradation (i.e., the polymer lasts
longer). In the past 15 years manufacturers have used these
polymers to develop biodegradable plates and screws for
craniofacial and hand applications. Each manufacturer has
modified the ratio of lactic and glycolic acid as well as the
specific manufacturing protocol to optimize the degradation
rate and strength of the polymer. For example, LactoSorb
(Biomet, Warsaw, IN) consists of 82% PLA and 18% PGA
while Resorb X (KLS Martin, Jacksonville, FL; used in Sonic­
Weld) is 100% poly D,L-lactic acid (PDLLA). At implanta­
tion, their strength is equal to that of titanium plating and
decreases with time. Typically the structural integrity is pre­
served for the first 8 weeks to allow for bony healing to
occur.
Vicryl knitted meshes are used as a temporary abdomino­
fascial closure in complex abdominal wall reconstruction,
particularly in a contaminated wound. The mesh helps contain
the viscera initially and subsequently resolves, creating an
iatrogenic hernia that is repaired in a delayed stage.

601
Skin substitutes
BOX 30.2  Characteristics of the ideal tissue adhesive
Must be safe (i.e., no allergic response, disease transmission)
Must eliminate potential spaces
Must be easy to use
Must be cost-effective
Must have a clinical benefit
centrifugation. The platelet layer, which also contains native
fibrinogen, is then combined with bovine thrombin, resulting
in a gel adhesive. This product is good for individuals who
do not want to use the commercially available fibrin sealant.
It is also less expensive to manufacture (once the initial equip­
ment is accounted for) than the commercially produced fibrin
sealants. There are, however, some drawbacks to this product.
The concentration of fibrinogen in PRP is significantly lower
than in the commercially available fibrin sealants. Thus, the
PRP is a less effective adhesive. In addition, the tensile strength
and hemostatic capabilities of PRP are also lower than the
commercially available products. The clinical applications of
this product include brow lift, facelift, abdominoplasty, the
latissimus dorsi donor site, and deep inferior epigastric
perforator/transverse rectus abdominis myocutaneous flap
donor sites, where there is a large surface area that the surgeon
would like to adhere together. Spray or mist applicators
provide the best delivery method.
Fibrin tissue adhesives
Fibrin sealants were the first FDA-approved tissue adhesives
and consist of two parts: fibrinogen and thrombin. A small
amount of factor XIII and calcium is included to catalyze
the reaction and form polymerized fibrin. Screened donors
provide pooled human plasma as the source of the two ingre­
dients. The commercially available product also contains an
antifibrinolytic to decrease degradation and bovine-derived
aprotinin, which acts as a stabilizer. In order to prevent disease
transmission, the products undergo heat pasteurization and
ultrafiltration.
The product must be refrigerated and requires approxi­
mately 20 minutes to prepare. The two bottles need to be
placed in a special warmer for several minutes. Once heated,
the components are drawn up into individual syringes. The
dual syringe delivery system is designed to mix the two
ingredients immediately before they are applied. There are
multiple delivery mechanisms available. The simplest deliv­
ery system is a straight blunt-tipped needle. There are also
sprayer/mister applicators and applicators for endoscopic
use. The misters provide the maximal mixing of the two
components and produce the thinnest layer of polymerized
fibrin to the wound, which has been shown to have the stron­
gest adhesive properties.31
The strength of the fibrin glue is directly proportional
to the concentration of fibrinogen in the mixture while the
rate of polymerization is regulated by the concentration
of the thrombin. Thus, in applications where the tissues need
to be manipulated (e.g., a large flap), a lower concentration of
thrombin should be used. Plastic surgery applications for
fibrin sealants are similar to the indications for PRP described
above. Fibrin sealants have also been used successfully to
treat chronic seromas with percutaneous injection.32
Cyanoacrylate
The original cyanoacrylates were butyl-cyanoacrylate. The
butyl-cyanoacrylate is a short chain with rapid breakdown,
which resulted in many wounds dehiscing. In addition, the
breakdown products (formaldehyde and cyanoacetate) can
cause a severe inflammatory reaction if butyl-cyanoacrylate
penetrates the skin. In order to address these issues, octyl-
cyanoacrylates were developed. They have longer side chains,
creating a stronger and longer-lasting polymer. The polymer­
ization begins when the 2-octyl-cyanoacrylate is exposed to
moisture (there is enough moisture in the air to allow poly­
merization to occur). Applications in plastic surgery are
limited to skin closure. Because the superficial layer of the
skin, where the product is applied, will not have any sutures
to hold it together, it is important to make sure the deep layers
are well approximated and provide a tension-free abutment
of the two sides. Studies that have been done comparing
traditional suturing to using octyl-2-cyanoacrylate showed
that the outcomes were equivalent.33
Skin substitutes
Over the past 25 years, bioengineered skin substitutes have
become a mainstream therapy for wound management.34
Originally designed to replace skin grafts for patients with
severe burns, their use has broadened to include the treatment
of chronic venous and chronic diabetic ulcers. As these tech­
nologies continue to advance, their application will broaden
even further (Box 30.3).
Although the ideal skin substitute does not exist, engineers
and scientists have developed, and continue to refine, several
very useful products. The engineering of cultured skin sub­
stitutes has been developed on the premise that three impor­
tant components are required for their formation: (1) a cell
source; (2) a “tissue differentiation-inducing” substance; and
(3) a matrix.35 A variety of cells, mediators, and polymers have
been tested in various combinations to engineer cultured skin
substitutes. We review the most common of these below and
compare them in Table 30.3.
Integra
Integra (Integra LifeSciences, Plainsboro, NJ) is a bilayer skin
substitute. The “dermal” (lower) layer is a bovine collagen
BOX 30.3  Characteristics of an ideal skin substitute
Adhere to the wound bed rapidly
Recapitulate the physiologic and mechanical properties of normal
skin
Be inexpensive
Avoid immune rejection by the host
Be highly effective in accelerating tissue regeneration and wound
repair.

602
CHAPTER 30 • Implants and biomaterials
base with glycosaminoglycan chondroitin-6-sulfate while the
upper layer is a silicone sheet that acts as a temporary epider­
mis.36 As the wound heals the dermal layer is replaced with
the patient’s own cells.37 A thin split-thickness skin graft is
then applied on to the neodermis. Integra is indicated for the
management of complex wounds such as partial- or full-
thickness burns, and multiple types of ulcer. Several studies
have evaluated the efficacy of Integra and have compared
Integra with autograft, allograft, xenograft or Biobrane. Bio­
brane (Smith & Nephew, Largo, FL) is a biosynthetic dressing
constructed of a silicone film with a collagen-bound nylon
fabric partially embedded into the film. These studies showed
that Integra has a higher rate of infection than the other
tested product with regard to wound infection and graft
take. However, Integra appeared to be better than autograft,
allograft, or xenograft in terms of wound-healing time. Integra
is also used in complex wounds to which a skin graft would
not adhere.36,38,39 The neodermis attaches to the underlying
bed, vascularizes over 10–14 days, and then provides a surface
for a split-thickness skin graft to adhere to.
Epicel (cultured epidermal autografts)
Epicel (Vericel Corp., Cambridge, MA) is a cultured epidermal
autograft grown from the patient’s own keratinocytes. A small
skin biopsy is harvested from the patient and sent to the
company for processing. The keratinocytes are grown in a
co-culture using proliferation-arrested, 3T3 murine fibroblast
feeder cells. Once the keratinocytes are 2–8 cell layers thick
the autograft is returned to the patient for grafting. The graft
is attached to petrolatum gauze backing with stainless steel
surgical clips and measures approximately 50 cm2.
Epicel is indicated for patients who have either deep dermal
or full-thickness burns involving a total body surface area of
greater than or equal to 30%. It can be used in conjunction
with split-thickness skin grafts, or alone in patients for whom
split-thickness skin grafts may not be an option due to the
severity and extent of their burns. Epithelial cells have been
Table 30.3  Comparison of commercially available skin substitutes
Product
Company
Tissue of origin
Layers
Uses
Integra
Integra Life Sciences
Plainsboro, NJ
Synthetic
1. Silicone
2. Collagen and GAG matrix
Deep- or full-thickness soft-tissue
defects for coverage
Requires skin graft
Epicel
Vericel Corp.
Cambridge, MA
Autogenous
Cultured autogenous
keratinocytes
Deep partial- and full-thickness burns
>30% TBSA
Dermagraft
Organogenesis
Canton, MA
Allogeneic dermis
Vicryl seeded with neonatal
fibroblasts
Chronic wounds
Full-thickness burns with STSG
Apligraf
Organogenesis
Canton, MA
Allogeneic composite
1. Neonatal keratinocytes
2. Collagen seeded with
neonatal fibroblasts
Chronic wounds
Excision sites
Used with STSG to improve function/
cosmesis
AlloDerm
LifeCell
Branchburg, NJ
Allogeneic dermis
Acellular dermis
Deep partial- and full- thickness burns
Soft-tissue replacement
Suspensory materials
Interpositional grafts
Tissue patches
GAG, glycosaminoglycan; STSG, split-thickness skin graft; TBSA, total body surface area.
(Adapted from Shores JT, Gabriel A, Gupta S. Skin substitutes and alternatives: a review. Adv Skin Wound Care. 2007;20:493–508; quiz 509–510.)
combined with Integra to regenerate skin and oral mucosa
successfully in animal models. This has been performed
with cultured epidermal autograft placed over vascularized
Integra,40 preseeding keratinocytes into the Integra, and
applied in a single stage.41–44
Dermagraft
Dermagraft (Organogenesis, Canton, MA) is a polyglactin
mesh seeded with neonatal fibroblasts. The fibroblasts produce
collagen, glycosaminoglycans, fibronectin, and other growth
factors. Over time the mesh is resorbed and replaced with the
patient’s own tissue.37 Dermagraft has applications as both a
temporary and permanent covering to increase the successful
take of meshed split-thickness skin grafts on excised burn
wounds and for venous ulcers and pressure ulcers.37,45 With
respect to infection, exudate, healing time, time to closure,
and graft take, Dermagraft has been shown to be equivalent
to allograft.45–47
Apligraf
Apligraf (Organogenesis, Canton, MA) is a bilayered skin-
equivalent. The lower “dermal” layer consists of type I bovine
collagen and fibroblasts obtained from neonatal foreskin. The
upper “epidermal” layer is derived from keratinocytes. It has
to be applied “fresh” and has a shelf-life of 5 days at room
temperature.37 It has been used to cover and help heal venous
ulcers and diabetic foot ulcers. It has been used as a temporary
covering over meshed expanded autograft for excised burn
wounds.48
Bioprosthetic mesh
To avoid the possible side effects of synthetic prosthetic
mesh and provide a more biocompatible material, biopros­
thetic materials have been developed and used for multiple

603
Bioprosthetic mesh
Biodesign to reflect the significant improvements that had
been made to the biomaterial.
Human acellular dermal matrix
Human acellular dermal matrix (HADM) (AlloDerm, LifeCell,
Branchburg, NJ; Allomax, Bard Davol, Murray Hill, NJ; and
FlexHD, Ethicon360, Somerville, NJ) is made from donated
allograft human dermis. Each manufacturer has a proprietary
technique for producing the acellular dermal matrix. In
general the epidermis and subcutaneous tissue are removed
and the dermis is processed, with either freeze-drying or
chemical detergents, resulting in the collagen structure of the
dermal matrix. Applications of HADM include implant-based
breast, abdominal wall, chest wall, and pelvis reconstruction,
and lip augmentation. Micronized HADM (Cymetra, LifeCell,
Branchburg, NJ) is also available and has been used for laryn­
goplasty and as a soft-tissue filler.
Porcine acellular dermal matrix
Porcine acellular dermal matrix (PADM) has been developed
for applications similar to HADM. Porcine materials are more
abundant and it is easier to control the harvesting conditions.
However, because the PADM is from a xenogeneic source,
additional processing must occur to prevent an adverse
immunogenic reaction when implanted in humans. To inhibit
immunogenicity and reduce collagenase-dependent matrix
degradation, first-generation PADMs (CollaMend, Davol
Bard, Warwick, RI and Permacol, Covidien-Medtronic, Min­
neapolis, MN) undergo intentional chemical cross-linking of
collagen fibers during the manufacturing process. A second­
ary side effect of the cross-linking is the alteration of the
extracellular matrix structure, which has been shown to
inhibit cellular infiltration, revascularization, and matrix
remodeling potential.61
A newer generation of PADM (Strattice, LifeCell, Branch­
burg, NJ), is processed without chemical cross-linking. In this
case, the [galactose-α(1,3)-galactose] antigen, which is the
major cause of the immune response associated with acellular
xenografts, is enzymatically removed.
It is not entirely clear which of these products has a
better outcome; however, in a recent in vivo animal study
comparing cross-linked PADM to noncross-linked PADM for
abdominal wall reconstruction, the noncross-linked PADM
was rapidly infiltrated with host cells and vessels while cross-
linked PADM became encapsulated. Noncross-linked PADM
had weaker adhesions to repair sites while it increased the
mechanical strength of the bioprosthesis–musculofascia inter­
face at early timepoints. Thus, the study concluded that
noncross-linked PADM may have early clinical advantages
over cross-linked PADM for bioprosthetic abdominal wall
reconstruction.62 However, no comparative human studies
have been performed to date.
Other bioprosthetic mesh products
Bovine pericardium (Veritas, Baxter Healthcare Corp.,
Deerfield, IL) collagen matrix is a noncross-linked bovine
pericardium. The decellularization and reduction of the
immunogenicity are achieved by capping free amine groups
using a proprietary chemical process.
applications. Currently available bioprosthetic mesh materi­
als are derived from decellularized mammalian tissues, either
human (allogeneic) or animal (xenogeneic). Dermis is the
most common source tissue for bioprosthetic meshes. Bio­
prosthetic mesh materials are processed to remove cells, cel­
lular debris, and other potentially immunogeneic components
optimally without disrupting the native extracellular matrix
(e.g., collagen, proteoglycan) architecture. Preservation of the
native extracellular matrix is important to allow these materi­
als to remodel and regenerate (gradually being replaced with
native host tissue) rather than become scarred and encapsu­
lated by the body. An ideal mesh should possess the charac­
teristics shown in Box 30.4.
There are a growing number of bioprosthetic mesh materi­
als available from which the surgeon can select. Many of these
materials are used for complex torso reconstruction, including
breast reconstruction, chest wall reconstruction and ventral
hernia repair.49 They are often selected over synthetic mesh
owing to their ability to resist infection.50 They limit repair site
adhesions51,52 and tolerate cutaneous exposure, usually
without the need to remove the bioprosthetic mesh.
Small intestinal submucosa
Small intestinal submucosa (SIS) (Biodesign, Cook Biotech,
West Lafayette, IN) is a biomaterial created from the small
intestine of pigs. After removal of the mucosal, serosal, and
muscular layers of the small intestine, a strong, collagenous
matrix remains. The submucosa of the small intestine pro­
vides mechanical strength to the intestine. The strong, yet
biochemically rich and diverse extracellular matrix of the
submucosa makes it an excellent choice for a naturally
derived biomaterial. First described as a vascular graft in
1989,53 SIS has been applied to over 20 applications in
humans, including multiple types of hernia repair,54–56 dural
repair,57 bladder reconstruction,58,59 and stress urinary incon­
tinence treatment.60 Originally released in 1989 as Surgisis,
this biomaterial has undergone several revisions to allow
better integration of the host tissue. In 2008, it was renamed
BOX 30.4  Characteristics of the ideal bioprosthetic mesh
Resistance to bacterial colonization and chronic infection
Biocompatibility and noncarcinogenicity
Available readily at acceptable cost
Ability to withstand physiological stresses over a long period of time
No additional pain caused after implantation
Promotion of strong tissue ingrowth
Avoidance of substantial contraction or expansion after
implementation
Limits development of adhesions to visceral structures induced
Provides cells with a supportive framework and the necessary
signals for host cells to grow, differentiate, and interact, while at
the same time it should become remodeled as the wound gains
strength and new tissue is formed
(Adapted from Bellows CF, Alder A, Helton WS. Abdominal wall reconstruction
using biological tissue grafts: present status and future opportunities. Exp Rev
Med Devices. 2006;3:657–675.)

604
CHAPTER 30 • Implants and biomaterials
be used as an injectable connective tissue matrix. All of
these products are stored at room temperature with a 5-year
shelf-life. Grafix (Osiris Therapeutics, Columbia, MD) is a
cryopreserved placental membrane, which, like the products
mentioned above, is made up of extracellular matrix and
growth factors/cytokines. However, this product also contains
cells native to the tissue (which include epithelial cells, fibro­
blasts, and stem cells). It is used to help heal wounds. As it is
a frozen product, it needs to be thawed prior to being used.
Future materials
Biomaterials and implants have made huge impacts on medi­
cine and surgery. Some implants are designed to have as little
impact or interaction with the body as possible. Others are
designed to interact with the body in a passive way (e.g.,
biodegradable PLGA polymers). The most recent biomaterials
are being designed to modulate their environment to create a
tissue-specific response. Furthermore, hybrid biomaterials
containing cells, polymers, and growth factors are currently
being developed in in vivo models. These biomaterials will
eventually be able to “sense” their surroundings and change
their biochemical and mechanical properties in response to
the needs of the environment. As with the past development
of biomaterials, the continued progress of the biomaterial field
depends upon an interdisciplinary collaboration between
engineers, scientists, clinicians, and industry. With continued
cooperation between these biomaterials experts, the future
use of biomaterials and implants in plastic surgery will likely
change significantly in the future. The goal would be to manu­
facturer materials with specific properties to reconstruct site-
specific defects individualized to the exact biologic, chemical,
and functional needs of the reconstruction.
Bovine fetal dermis (Surgimend and Primatrix, Integra Life
Sciences (formerly TEI), Plainsboro, NJ) is an acellular dermal
matrix derived from fetal calves. It is not cross-linked and can
facilitate cell penetration, revascularization, and integration
with host tissues.
Amniotic/placental-based materials
Amnion has been used as a biomaterial for over 100 years.
Its first published use as a skin graft occurred in 1910 and
its first use in burn patients in 1912.63–65 The amniotic mem­
brane is a monolayer of epithelial cells, a thick basement
membrane, and an avascular matrix. This epithelium manu­
factures multiple cytokines and growth factors. The amnion
has been reported to promote epithelialization while main­
taining antimicrobial, immunogenicity, and analgesic pro­
perties. Many of the properties are preserved even after
de-epithelialization and sterilization of the amnion. Due to
these factors, amnion has biological and mechanical properties
that make it useful as a valuable dressing material.63,66 Over
the past few years several companies have developed products
derived from either human placental, amnionic or chorionic
tissue. BioFix (Integra LifeSciences, Plainsboro, NJ) and
AmnioFix (MiMedx, Marietta, GA) are sterile, dehydrated and
decellularized amniotic membrane. They are used to cover
wounds and to fill tissue defects. BioFix Plus (Integra Life­
Sciences, Plainsboro, NJ) and EpiFix (MiMedx, Marietta, GA)
are similar products but these also include the chorion. These
products require no preparation and can be placed on the
wound with either side up. One of these companies has also
released a particulate human decellularized placental connec­
tive tissue matrix (BioFix Flow, Integra LifeSciences, Plains­
boro, NJ). This product comes in a syringe and is designed to
4. Cumberland VH. A preliminary report on the use of prefabricated
nylon weave in the repair of ventral hernia. Med J Aust.
1952;1:143–144.
5. Scales JT. Materials for hernia repair. Proc R Soc Med. 1953;46:647–
652. These manuscripts offer a discussion of the ideal physical properties
of synthetic surgical implants. The notion that host response can be
modulated by altering these properties of the synthetic is discussed.
18. Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of the relation
between silicone breast implants and the risk of connective-tissue
diseases. N Engl J Med. 2000;342:781–790. This report offers a
meta-analysis of studies investigating a causal connection between silicone
breast prostheses and connective tissue disorders. No connections between
breast implants and connective tissue, rheumatic or autoimmune diseases
were identified.
32. Butler CE. Treatment of refractory donor-site seromas with
percutaneous instillation of fibrin sealant. Plast Reconstr Surg.
2006;117:976–985.
33. Toriumi DM, O’Grady K, Desai D, et al. Use of octyl-2-
cyanoacrylate for skin closure in facial plastic surgery. Plast Reconstr
Surg. 1998;102:2209–2219. Octyl-2-cyanoacrylate was compared to
conventional sutures in 111 elective surgical procedures by a single
surgeon. A significantly superior cosmetic outcome was reported at 1 year
in the skin glue group.
35. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–926.
36. Pham C, Greenwood J, Cleland H, et al. Bioengineered skin
substitutes for the management of burns: a systematic review.
Burns. 2007;33:946–957. This review examined 20 randomized control
trials to compare the safety and efficacy of bioengineered skin substitutes
to biological skin replacements. The authors found that sufficient evidence
was not present in the literature to draw definitive conclusions, and urged
further study on this topic.
39. Heimbach D, Luterman A, Burke J, et al. Artificial dermis for major
burns. A multi-center randomized clinical trial. Ann Surg.
1988;208:313–320. This series details the early use of artificial dermal
grafts. The authors conclude that artificial dermal grafts coupled with
epidermal grafts offer coverage comparable to conventional skin grafts
with less donor site morbidity.
50. Breuing K, Butler CE, Ferzoco S, et al. Incisional ventral hernias:
review of the literature and recommendations regarding the
grading and technique of repair. Surgery. 2010;148:544–558.
Access the complete reference list online at

604.e1
References
References
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3. Scott M. 32 000 years of sutures. NATNEWS. 1983;20:15–17.
4. Cumberland VH. A preliminary report on the use of prefabricated
nylon weave in the repair of ventral hernia. Med J Aust.
1952;1:143–144.
5. Scales JT. Materials for hernia repair. Proc R Soc Med. 1953;46:647–
652. These manuscripts offer a discussion of the ideal physical properties
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modulated by altering these properties of the synthetic is discussed.
6. Holmes RE. Alloplastic materials. In: McCarthy JG, ed. Plastic
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8. Luckey HA, Kubli F, eds. Titanium alloys in surgical implants, a STM
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12. Olszewski U, Hamilton G. A better platinum-based anticancer drug
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13. Food and Drug Administration. FDA breast implant consumer
handbook – 2004. Washington, DC: Food and Drug Adminstration;
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14. Bondurant S, Ernster V, Herdman R. Safety of silicone breast implants.
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15. Bondurant S, Ernster V, Herdman R, eds. Safety of silicone breast
implants. Washington, D. C.: Institute of Medicine, National
Academy Press; 1999.
16. Brody GS, Long JN. Breast implants, safety and efficacy of silicone.
<>;2009.
17. Brinton LA, Malone KE, Coates RJ, et al. Breast enlargement and
reduction: results from a breast cancer case-control study. Plast
Reconstr Surg. 1996;97:269–275.
18. Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of the relation
between silicone breast implants and the risk of connective-tissue
diseases. N Engl J Med. 2000;342:781–790. This report offers a
meta-analysis of studies investigating a causal connection between silicone
breast prostheses and connective tissue disorders. No connections between
breast implants and connective tissue, rheumatic or autoimmune diseases
were identified.
19. Nicolai JP. EQUAM declaration on breast implants, July 4, 1998.
European Committee on Quality Assurance and Medical Devices in
Plastic Surgery. Plast Reconstr Surg. 1999;103:1094.
20. Keech JA Jr, Creech BJ. Anaplastic T-cell lymphoma in proximity to
a saline-filled breast implant. Plast Reconstr Surg. 1997;100:554–555.
21. U.S. Food and Drug Administration. Reports of Anaplastic Large Cell
Lymphoma (ALCL) in Women with Breast Implants: FDA Safety
Communication. <
AlertsandNotices/ucm240000.htm>; 2011.
22. U.S. Food and Drug Administration. Anaplastic Large Cell Lymphoma
(ALCL). 2016. <
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BreastImplants/ucm239995.htm>; 2016.
23. Clemens MW, Miranda RN. Coming of age: breast implant-
associated anaplastic large cell lymphoma after 18 years of
investigation. Clin Plast Surg. 2015;42:605–613.
24. Kadin ME, Deva A, Xu H, et al. Biomarkers provide clues to early
events in the pathogenesis of breast implant-associated anaplastic
large cell lymphoma. Aesthet Surg J. 2016;36:773–781.
25. U.S. Food and Drug Administration. Regulatory history of breast
implants in the U.S. <
ProductsandMedicalProcedures/ImplantsandProsthetics/
BreastImplants/ucm064461.htm>; 2016.
26. DuPont. Roy Plunkett: 1938. <
functions/our-company/dupont-history.html>; 2011.
27. Panossian A, Garner WL. Polytetrafluoroethylene facial implants: 15
years later. Plast Reconstr Surg. 2004;113:347–349.
28. Schultz DG. FDA public health notification: serious complications
associated with transvaginal placement of surgical mesh in repair of pelvic
organ prolapse and stress urinary incontinence. Washington, DC: Food
and Drug Administration; 2008.
29. Kohn J, Abramson S, Langer R. Bioresorbable and bioerodible
materials. In: Ratner BD, Hoffman AS, Schoen FJ, et al., eds.
Biomaterials Science: An Introduction to Materials in Medicine. San
Diego: Elsevier Academic Press; 2004:115–125.
30. Egan KK, Kim DW, Toriumi DM. Tissue adhesives. In: Papel I, ed.
Facial Plastic and Reconstructive Surgery. New York: Thieme;
2009:91–97.
31. O’Grady KM, Agrawal A, Bhattacharyya TK, et al. An evaluation of
fibrin tissue adhesive concentration and application thickness on
skin graft survival. Laryngoscope. 2000;110:1931–1935.
32. Butler CE. Treatment of refractory donor-site seromas with
percutaneous instillation of fibrin sealant. Plast Reconstr Surg.
2006;117:976–985.
33. Toriumi DM, O’Grady K, Desai D, et al. Use of octyl-2-
cyanoacrylate for skin closure in facial plastic surgery. Plast Reconstr
Surg. 1998;102:2209–2219. Octyl-2-cyanoacrylate was compared to
conventional sutures in 111 elective surgical procedures by a single
surgeon. A significantly superior cosmetic outcome was reported at 1 year
in the skin glue group.
34. Eisenbud D, Huang NF, Luke S, et al. Skin substitutes and wound
healing: current status and challenges. Wounds. 2004;16(1).
35. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–926.
36. Pham C, Greenwood J, Cleland H, et al. Bioengineered skin
substitutes for the management of burns: a systematic review.
Burns. 2007;33:946–957. This review examined 20 randomized control
trials to compare the safety and efficacy of bioengineered skin substitutes
to biological skin replacements. The authors found that sufficient evidence
was not present in the literature to draw definitive conclusions, and urged
further study on this topic.
37. Hansen SL, Voigt DW, Wiebelhaus P, et al. Using skin replacement
products to treat burns and wounds. Adv Skin Wound Care.
2001;14:37–44, quiz 5–6.
38. Peck MD, Kessler M, Meyer AA, et al. A trial of the effectiveness of
artificial dermis in the treatment of patients with burns greater than
45% total body surface area. J Trauma. 2002;52:971–978.
39. Heimbach D, Luterman A, Burke J, et al. Artificial dermis for major
burns. A multi-center randomized clinical trial. Ann Surg.
1988;208:313–320. This series details the early use of artificial dermal
grafts. The authors conclude that artificial dermal grafts coupled with
epidermal grafts offer coverage comparable to conventional skin grafts
with less donor site morbidity.
40. Orgill DP, Butler C, Regan JF, et al. Vascularized collagen-
glycosaminoglycan matrix provides a dermal substrate and
improves take of cultured epithelial autografts. Plast Reconstr Surg.
1998;102:423–429.
41. Butler CE, Orgill DP, Yannas IV, et al. Effect of keratinocyte seeding
of collagen-glycosaminoglycan membranes on the regeneration of
skin in a porcine model. Plast Reconstr Surg. 1998;101:1572–1579.
42. Compton CC, Nadire KB, Regauer S, et al. Cultured human
sole-derived keratinocyte grafts re-express site-specific
differentiation after transplantation. Differentiation. 1998;64:45–53.
43. Butler CE, Yannas IV, Compton CC, et al. Comparison of cultured
and uncultured keratinocytes seeded into a collagen-GAG matrix
for skin replacements. Br J Plast Surg. 1999;52:127–132.
44. Butler CE, Navarro FA, Park CS, et al. Regeneration of neomucosa
using cell-seeded collagen-GAG matrices in athymic mice. Ann
Plast Surg. 2002;48:298–304.
45. Hansbrough JF, Mozingo DW, Kealey GP, et al. Clinical trials of a
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Covering, compared with cryopreserved human cadaver skin for
temporary coverage of excised burn wounds. J Burn Care Rehabil.
1997;18:43–51.
46. Spielvogel RL. A histological study of Dermagraft-TC in patients’
burn wounds. J Burn Care Rehabil. 1997;18:S16–S18.
47. Purdue GF, Hunt JL, Still JM Jr, et al. A multicenter clinical trial of a
biosynthetic skin replacement, Dermagraft-TC, compared with
cryopreserved human cadaver skin for temporary coverage of
excised burn wounds. J Burn Care Rehabil. 1997;18:52–57.
48. Waymack P, Duff RG, Sabolinski M. The effect of a tissue
engineered bilayered living skin analog, over meshed split-
thickness autografts on the healing of excised burn wounds. The
Apligraf Burn Study Group. Burns. 2000;26:609–619.
49. Butler CE, Langstein HN, Kronowitz SJ. Pelvic, abdominal, and
chest wall reconstruction with AlloDerm in patients at increased
risk for mesh-related complications. Plast Reconstr Surg.
2005;116:1263–1275, discussion 76–77.
50. Breuing K, Butler CE, Ferzoco S, et al. Incisional ventral hernias:
review of the literature and recommendations regarding the
grading and technique of repair. Surgery. 2010;148:544–558.
51. Burns NK, Jaffari MV, Rios CN, et al. Noncross-linked porcine
acellular dermal matrices for abdominal wall reconstruction. Plast
Reconstr Surg. 2010;125:167–176.
52. Butler CE, Prieto VG. Reduction of adhesions with composite
AlloDerm/polypropylene mesh implants for abdominal wall
reconstruction. Plast Reconstr Surg. 2004;114:464–473.
53. Badylak SF, Lantz GC, Coffey A, et al. Small intestinal submucosa
as a large diameter vascular graft in the dog. J Surg Res.
1989;47:74–80.
54. Oelschlager BK, Pellegrini CA, Hunter J, et al. Biologic prosthesis
reduces recurrence after laparoscopic paraesophageal hernia repair:
a multicenter, prospective, randomized trial. Ann Surg.
2006;244:481–490.
55. Helton WS, Fisichella PM, Berger R, et al. Short-term outcomes with
small intestinal submucosa for ventral abdominal hernia. Arch Surg.
2005;140:549–560, discussion 60–62.
56. Ansaloni L, Catena F, D’Alessandro L. Prospective randomized,
double-blind, controlled trial comparing Lichtenstein’s repair of
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tissue graft: preliminary results. Acta Biomed. 2003;74(suppl
2):10–14.
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59. Landman J, Olweny E, Sundaram CP, et al. Laparoscopic mid
sagittal hemicystectomy and bladder reconstruction with small
intestinal submucosa and reimplantation of ureter into small
intestinal submucosa: 1-year followup. J Urol. 2004;171:2450–2455.
60. Wiedemann A, Otto M. Small intestinal submucosa for
pubourethral sling suspension for the treatment of stress
incontinence: first histopathological results in humans. J Urol.
2004;172:215–218.
61. Butler CE. The role of bioprosthetics in abdominal wall
reconstruction. Clin Plast Surg. 2006;33:199–211, v–vi.
62. Butler CE, Burns NK, Campbell KT, et al. Comparison of cross-
linked and noncross-linked porcine acellular dermal matrices for
ventral hernia repair. J Am Coll Surg. 2010;211:368–376.
63. Kesting MR, Wolff KD, Hohlweg-Majert B, Steinstraesser L. The
role of allogenic amniotic membrane in burn treatment. J Burn Care
Res. 2008;29:907–916.
64. Davis J. Skin transplantation with a review of 550 cases at the Johns
Hopkins Hospital. Johns Hopkins Hosp Rep. 1910;15:310.
65. Sabella N. Use of the fetal membranes in skin grafting. Med Rec NY.
1913;83:478.
66. Litwiniuk M, Grzela T. Amniotic membrane: new concepts for an
old dressing. Wound Repair Regen. 2014;22:451–456.

31 
Facial prosthetics in plastic surgery
Gordon H. Wilkes, Mohammed M. Al Kahtani, Johan F. Wolfaardt, and Lindsay D. McHutchion
SYNOPSIS
■ The success of osseointegration biotechnology has revolutionized
facial prosthetic reconstruction.
■ Titanium is the implant material of choice as it is light, biocompatible,
and resistant to corrosion.
■ Implant placement technique is crucial to produce bone–implant
contact with no interposed fibrous tissue and successful bone healing.
■ Appropriate treatment selection requires understanding of all options
available.
■ Multidisciplinary team planning is required.
■ Osseointegration biotechnology provides plastic surgeons with more
treatment options for challenging head and neck deformities.
Deformities in the head and neck region can have a profound
effect on the function, aesthetics, and psyche of an individual.
Considerable time, effort, and ingenuity have been spent
trying to develop meaningful reconstructive solutions to a
wide variety of craniofacial defects. Autogenous reconstruc­
tion remains the gold standard, but in certain cases, autogenous
reconstruction may be contraindicated, technically impossible,
or have the potential to solve the reconstructive issues only
partially.
Historically facial prosthetics have been of limited benefit.
Retention of facial prostheses has been largely unsuccessful
because of the need for adhesives or crude mechanical means
of maintaining retention. The patient lacked confidence about
the positioning of the prosthesis and its ability to stay in place.
Often associated pain or discomfort would limit the length of
time and circumstances in which the prosthesis would actually
be worn. The adhesives are those used in industry and were
not developed for the unique sensitive human biological
environment. They often had adverse effects on the underlying
skin compromised by radiotherapy, trauma, or thermal injury1
and affected the durability and longevity of the prosthesis.
With the success of osseointegration and its ability to
solve the problem of prosthetic retention,2,3 a new treatment
modality was now available.4,5 Prosthetic longevity is
increased without the need for adhesives.6,7 Osseointegrated
facial prosthetics now meet the necessary criteria for success:
(1) aesthetic acceptability; (2) functional performance; (3)
biocompatibility; and (4) desired retention.8 The use of osseo­
integration biotechnology in facial prosthetic restoration has
been hailed as the most significant advance in the field of
facial prosthetics in the past 28 years.9 It is estimated that more
than 90 000 implants have been installed extraorally in more
than 45 000 patients up to the year 2007.10 Craniofacial osseo­
integrated reconstruction gives the plastic surgeon another
viable treatment option in many challenging head and neck
defects.11 It can provide some patients with a meaningful and
enhanced quality of life when in the past other treatment
options would not have been successful. Unfortunately, com­
peting specialties or providers have presented autologous
techniques and craniofacial osseointegration as unrelated
technologies.12 Osseointegrated and autogenous techniques
should not be viewed as competing technologies, but rather
as complementary reconstructive procedures that optimize
the opportunity for success in the management of major head
and neck deformities.
Why this situation has arisen is unclear. In some cases, it
appears to be due to a lack of understanding of osseointegra­
tion and its benefits. It may be viewed only as a salvage
procedure when all else has failed and both the patient and
surgeon are desperate. It is not viewed as “real” surgery, only
as throwing a few screws in the bone. Those in doubt cannot
understand how patients would be satisfied with a prosthesis,
“a foreign object that never becomes part of their body image”.
To any surgeon with experience in osseointegration, these
lines of thinking are seriously flawed.
This intervention requires long-term support by both the
caregiver and the funder for maintenance of the implant sites
as well as future prosthetic construction. It is analogous to the
time and financial commitment required in an organ trans­
plantation program.
  Access video lecture content for this chapter online at expertconsult.com

605.e1
Historical perspective
Historical perspective
Historically, implants in bone were largely unsuccessful and
had a poor reputation for long-term success. In the 1950s,
Professor Brånemark, from Goteborg, Sweden, discovered
titanium behaved somewhat differently from other metals
when in contact with bone. The term “osseointegration” was
coined by Brånemark in 1977.13 It is defined as the direct
contact – structural and functional – between ordered living
bone and the surface of a load-bearing implant. Osseointegra­
tion is a dynamic process that involves micromodeling at
periosteal and endosteal surfaces and remodeling at the
bone–implant interface.8,10,14 This principle of osseointegration
ultimately led to the development of successful dental
implants.15 The first osseointegrated implant was placed in a
human in 1965. Albrektsson et al. further postulated that a
skin-penetrating implant may be possible.16 Implants were
first placed in the mastoid region to support a bone-anchored
hearing aid in 1977 and to retain an auricular prosthesis in
197917 (Fig. 31.1). Subsequently, numerous reports have con­
firmed the efficacy and predictability of craniofacial osseoin­
tegration.18,19 The concept of anchoring craniofacial prostheses
on osseointegrated implants was accepted by the Food and
Drug Administration (FDA) in 1985. The FDA accepted the
concept of anchoring hearing aids on implants in adults in
Fig. 31.1  Historical development of osseointegration biotechnology. Through the
Brånemark experience, osseointegrated implants have been subjected to over 30
years of scientific scrutiny. Craniofacial applications were first introduced in 1977.
EO, extraoral.
1965
Development
period
1977 First bone-anchored
hearing aid implant
1979 First ear prosthesis implant
1984 International training,
EO implants available
1971
Standardization
period
1983
Innovation
1990
Intraoral osseointegration
Extraoral osseointegration
1995 and children in 1998. In 1985, implants were used in
hand surgery to anchor joint replacements and in the early
1990s the concept was used for anchoring prostheses in
amputees’ fingers, hands, arms, and legs.

606
CHAPTER 31 • Facial prosthetics in plastic surgery
Indications for craniofacial
osseointegration
Craniofacial osseointegration can be of particular benefit for
reconstruction of selected defects involving the ear, orbit,
nose, and combined midfacial defects. The osseointegrated
implants have also been used to secure hairpieces.21 A newer
application of interest to the plastic surgeon is the use of a
bone-anchored hearing aid (BAHA) in children with microtia.
In the past concern has been expressed combining a BAHA
and an autogenous ear reconstruction. Fear of inappropriate
positioning of the implant adversely affecting future autoge­
nous ear reconstruction usually prevented patients having the
benefits of both treatment modalities. This usually resulted in
the BAHA being placed too far posterior or not being consid­
ered at all. Certainly the BAHA is an excellent option for
hearing restoration in bilateral microtia patients and more
recently has proven of benefit in unilateral microtia patients
(Fig. 31.2). It is a much more straightforward, safe, and pre­
dictable way of improving hearing than previous autogenous
means of canalplasty and middle-ear reconstruction.10
Ear reconstruction
Autogenous reconstruction of auricular defects has improved
greatly in the latter half of the 20th century because of
the work of pioneers such as Tanzer,22 Brent,23–26 Fukada
and Yamada,27 Cronin,28 Bauer,29 Yanai et al.,30 Isshiki et al.,31
Nagata,32–34 and others. Certainly, not all reconstructive
attempts are successful. The appropriate treatment selection
for major ear defects continues to be controversial (Table
31.1).20 Certain auricular defects have limited autogenous
BOX 31.1  Advantages of craniofacial osseointegration7
Procedures short
Minimal morbidity
Minimal postoperative pain
Outpatient procedures
Short learning curve
Allows examination of tumor resection site
Salvage of autogenous failures
Use in compromised tissues
Excellent prosthetic aesthetics
BOX 31.2  Disadvantages of craniofacial osseointegration7
Need for multidisciplinary team
Need for reliable, committed patient
Ongoing expense of prosthetic remakes and maintenance visits
Not one’s own tissue
Fig. 31.2  Bone-anchored hearing aid (BAHA) and autogenous ear reconstruction
for microtia.
Access the Historical Perspective section and Fig. 31.1
online at

Advantages of craniofacial
osseointegration
Craniofacial osseointegration has many advantages (Box
31.1).20 The surgical procedures are generally short with
minimal morbidity and are performed on an outpatient basis.
There is a short learning curve and results are predictable. The
patients usually have minimal postoperative discomfort.
Examination of the tumor resection site is easy and allows
early diagnosis of any tumor recurrence.
Craniofacial osseointegration can successfully salvage
a patient with a failed autogenous reconstruction and often
offers superior aesthetics. When compared with adhesive-
retained facial prosthetics, osseointegration offers predictable
prosthetic retention, increased prosthetic durability and life­
span, enhanced prosthetic aesthetics, ease of displacement,
no underlying skin damage, successful incorporation of the
prosthesis into the body image, and a happier, more satisfied
patient. Osseointegration can also be considered in diabetics
and smokers.
The disadvantages of craniofacial osseointegration include
the need for a larger multidisciplinary team with skills that
are often not freely available. Patients also require regular
maintenance visits and a new prosthesis every 2–5 years (Box
31.2).20 Lifetime ongoing costs can be an issue with some
insurance companies.

607
Indications for craniofacial osseointegration
osseointegration in the pediatric population. It also showed
an increased need for psychological support in many of these
patients. Our approach is to offer autogenous ear reconstruc­
tion to pediatric patients with microtia. Despite the potential
for difficult treatment selection decisions, we rarely find this
to be the case. Patients usually decide quite quickly after the
possibilities are discussed. It is rare for patients to change
their mind following further discussion.
The use of an adhesive-retained auricular prosthesis is very
limited and almost relegated to historical significance only. It
certainly cannot be considered a “test” for an osseointegrated
prosthesis. It offers none of the major advantages of implant-
retained prostheses such as ease of placement, predictable
retention, improved aesthetics, increased lifespan of the
prosthesis, and no ongoing insult to the skin.
Osseointegrated nasal reconstruction
Indications for osseointegrated nasal reconstruction include:
(1) failed autogenous reconstruction; (2) significant scarring
in potential autogenous donor sites;6 (3) tumor recurrence
following initial autologous reconstruction; and (4) patient
preference (Box 31.3). Because of the need for multiple
options, particularly after removal of the ear for cancer with
associated radiotherapy. It is our belief that these reconstruc­
tive
techniques
are
complementary
and
must
be
presented in this manner.8,12,20 Definite indications for osseoin­
tegrated auricular prosthetic reconstruction include: (1) fol­
lowing major cancer resection; (2) radiotherapy to the proposed
site of auricular reconstruction; (3) severely compromised
local tissue (Fig. 31.3); (4) patient preference; and (5) salvage
procedure for failed autogenous reconstruction. Relative
indications include: (1) microtia; (2) absence of the lower half
of the ear; and (3) patients with calcified costal cartilage.
Probably the most controversial indication for osseointe­
grated auricular reconstruction is microtia in children.
Although it is technically possible to place implants in chil­
dren as young as 3 years of age and early results are encourag­
ing, the follow-up in these situations is short. Because the use
of craniofacial osseointegrated implants requires removal of
any local ear remnants and produces scarring in the operative
field, future autogenous reconstruction options are very
limited. For these reasons, the use of osseointegrated auricular
reconstruction in the pediatric age group requires very careful
consideration by the clinician and family (Fig. 31.4). A publi­
cation by Zeitoun et al.35 outlines the difficulties seen using
Table 31.1  Indications for osseointegrated ear reconstruction7
Definitive
Relative
Major cancer resection
Radiotherapy
Severely compromised tissue
Patient preference
Failed autogenous
reconstruction
Potential craniofacial anomaly
Poor operative risk
Microtia – most controversial
Absence of lower half of the ear
Calcified costal cartilage
A
B
Fig. 31.3  (A–C) Reconstruction following severe electrical injury included cranioplasty, free-flap scalp coverage, and ear reconstruction with implant-retained prosthesis.
C
BOX 31.3  Indications for osseointegrated nasal reconstruction10
Failed autogenous reconstruction
Scarring at autogenous donor sites
Reconstruction following autogenous reconstruction because of
tumor recurrence
Patient preference
Medical contraindication to multistaged autogenous reconstruction

608
CHAPTER 31 • Facial prosthetics in plastic surgery
surgical stages and the greater variability in the ultimate
result with autogenous reconstruction, many patients with
total nasal loss opt for placement of implants and a nasal
prosthesis (Fig. 31.5). Certainly, there is less surgery involved
with less morbidity. There is no need for other donor sites,
and tumor surveillance is easy with prosthesis removal.8 The
application of “nontraditional” long zygomatic implants may
be useful in difficult situations of nasal reconstruction.36
Osseointegrated orbital reconstruction
Patients with loss of the orbit and orbital contents have very
poor autogenous reconstructive options (Box 31.4). Although
autogenous coverage may be necessary to cover important
neurological structures, in many cases it is provided only to
fill the residual orbital cavity. However, “filling the hole” does
not create an aesthetic result. It is in these situations that
Fig. 31.4  (A,B) Ear loss and severe local
tissue trauma secondary to dog attack in a
child. Reconstructed with implant-retained
prosthesis.
A
B
Fig. 31.5  (A–D) Nasal deformity following cancer resection reconstructed with implant-retained nasal prosthesis.
A
B
C
D
BOX 31.4  Indications for osseointegrated orbital reconstruction
Loss of orbit and orbital contents
Severe enophthalmos with compromised vision
Difficulty with an ocular prosthesis and significant eyelid distortion
secondary to trauma or radiotherapy that is not amenable to
autogenous correction
osseointegrated orbital reconstruction clearly has advantages
over autogenous reconstruction (Fig. 31.6). The aesthetic
results are far superior and again allow visualization for early
tumor recurrence. This approach could also be considered in
patients with severe enophthalmos and significantly compro­
mised vision. Less frequently, it can be considered in patients
with an ocular prosthesis and significant eyelid distortion

609
Indications for craniofacial osseointegration
A
Fig. 31.6  (A,B) This patient had an orbital exenteration for a neurofibroma of the
orbit and scalp and was reconstructed with latissimus dorsi free flap and skin graft.
Further reconstruction using an implant-retained orbital prosthesis achieved a more
aesthetic result.
B
secondary to trauma or radiotherapy that is not amenable to
autogenous correction. The hope for the future would be to
create an orbital prosthesis that can mimic movement of both
the lids and globe of the opposite normal eye.13
Midfacial reconstruction
Patients with complex facial defects that may include the
orbit, nose, and maxilla again have poor autogenous options
(Fig. 31.7). Craniofacial osseointegration offers significant
advantages. It enables examination of the postsurgical
Fig. 31.7  (A,B) This patient had an extensive basal cell carcinoma invading his
orbit, nasal region, and maxilla. After surgical extirpation, implants were later placed
and a naso-orbital prosthesis constructed. Autogenous options were poor.
A
B

610
CHAPTER 31 • Facial prosthetics in plastic surgery
titanium oxide layer on the implant surface to react with the
adjacent bone (its biocompatibility). The key to success is
what happens at this implant–tissue interface. The most suc­
cessful is commercially pure titanium, which is 99.75% pure.
This differs from the most commonly used titanium alloy,
which contains 90% titanium, 6% aluminum, and 4% vana­
dium, and exhibits much less satisfactory characteristics of
osseointegration.
Implant–tissue interface
Except for mechanical forces, all interactions between the
implant and host occur from physiochemical forces less than
1.0 mm from the surface. When the titanium implant is
exposed to oxygen and comes in contact with the host, a layer
of oxide is rapidly formed. It acts as a protective barrier and
prevents direct contact between the metal and its environ­
ment. The titanium oxide layer continues to grow with time
and creates a dynamic interface. The oxide layer is the bioac­
tive component of the implant. The microsurface characteris­
tics of the implant itself, including roughness, porosity, and
thread design, all influence its potential for successful osseo­
integration. A surface roughness of 100 µm or greater is
advantageous; an implant that has a very smooth surface will
result in poor integration, but with minor bone resorption. A
very rough surface will result in rapid integration, but second­
ary inflammation and resorption that can jeopardize integra­
tion later on.
The macrostructure of the implant has importance for
integration. Rounding the outer edges and spaces of a threaded
implant relieves stress concentration. A screw-shaped implant
often shows good primary stability, whereas a cone-shaped
implant might be lost because of initial micromovements and
hence poor stability.
A
Fig. 31.8  (A,B) This patient had a
recurrent basal cell carcinoma resulting in
resection of both orbits and the anterior
maxilla. After reconstruction with free fibular
and radial forearm flaps, a facial prosthesis
retained by anatomical undercuts and
eyeglasses was created as the patient did
not wish to proceed with osseointegration.
B
oncologic defect and allows for a very acceptable aesthetic
result. In the patient shown in Fig. 31.7 it allowed early detec­
tion of a recurrence on the posterior orbital wall. Treatment
consisted of surgical removal and reconstruction with a
temporo­parietal fascial flap and skin graft. The patient was
able to resume wearing his prosthesis again only 12 days after
surgery to resect the recurrence. Extraoral osseointegration in
combination with intraoral osseointegration may also result
in significantly improved functional results over conventional
prosthetic or autogenous techniques.
In some cases the extent of resection, the nature of the
reconstruction, and the quality and quantity of remaining
bone or patient preference may make an implant retained
prosthesis impractical or undesirable. Other means of reten­
tion may be used to hold a prosthesis in place with reasonable
aesthetic and functional results (Fig. 31.8).This could also be
a treatment alternative in a select group of patients being
considered for composite tissue allotransplantation or as an
interim measure prior to CTA.
Factors important to obtain
osseointegration13,37
Choice of implant material
Many materials have been considered for osseointegration.
Although other metals such as vanadium, tantalum, alumi­
num hydroxide, and ceramics like hydroxyapatite are known
to integrate with bone to a certain degree, titanium is
currently the material of choice.37 Titanium is relatively
light but stiffer than bone. Its springiness allows it to flex
with the bone. The most important factor is the ability of its

611
Surgical technique
forces once the implant has integrated. If forces are distributed
in the longitudinal direction, even very high loads can be
withstood by the implant during many years of function.
Treatment planning
Providing craniofacial osseointegration care requires a larger
multidisciplinary team than autologous reconstruction. The
core team should include appropriate surgical expertise,
including plastic surgery, otolaryngology, and oral surgery, a
prosthodontist, an anaplastologist, and appropriate nursing
and dental assistants. Careful preoperative assessment and
planning are crucial for the ultimate success of this clinical
endeavor. Only by having the full spectrum of team members
can the patient be presented with all appropriate options to
make a truly informed decision.
The treatment-planning process starts with a multidisci­
plinary consultation. Team members then formulate an
approach to each individual patient’s problem. The preopera­
tive workup includes charting, standardized preoperative
photographs and psychological profile. Preoperative assess­
ment allows an evaluation of bony sites for implant placement,
the presence of surrounding vital structures, general quality
of the bone, and overlying soft tissues. Radiologic examina­
tion, impressions of the defect and the corresponding normal
side, and three-dimensional images may be used during
digital treatment planning, medical modeling, and construc­
tion of surgical templates.41–43
The patient should have no systemic or local factors that
could significantly influence bone-remodeling capacity.44 Age
alone is not considered a contraindication. Patients as young
as 3 years of age or in their 80s have been successfully treated.
There should be no psychiatric or substance abuse conditions.
Smoking is a relative contraindication,45 as is radiotherapy,10,46,47
or chemotherapy.48 The literature on smoking and implant
survival involves dental implants and not craniofacial osseo­
integrated implants.49 A past history of radiotherapy requires
assessment for hyperbaric oxygen treatment before and after
implant placement to optimize the chance for successful
osseointegration.50–52 Patients must have a certain level of
cognitive, visual, and dexterous ability to maintain osseointe­
grated implants. They must also have reasonable geographic
accessibility to an osseointegration unit. Once the preopera­
tive workup and informed consent have been obtained,
treatment can begin.
In autologous reconstruction, the surgeon provides the final
result. This differs from osseointegration, where the surgeon
sets the stage for the final prosthetic result by the prosthodon­
tist or anaplastologist. This makes preoperative planning and
proper implant placement even more vital to ultimate treat­
ment success. Good communication between the surgeon and
prosthodontist or anaplastologist preoperatively and often
intraoperatively is critical. Implants placed in the wrong posi­
tion will compromise the final aesthetic and functional result
or make further implant placement necessary.
Surgical technique
The surgical approach as developed by Brånemark is a
meticulous multistep technique that may be performed in one
or two stages, depending on the clinical situation.53 Although
Fig. 31.9  Bone–titanium interface with only oxide layer and no interposed soft
tissue.
Titanium
Bone
Titanium
Bone
Connective tissue
Osseointegrated
Nonintegrated
Bone bed
The bone bed into which the implant is installed is of impor­
tance. There is a difference if the implant is installed in a child
with relatively soft and immature bone, compared with an
adult. The older patient with osteoporosis will integrate the
implant to a lesser degree, and implant failure rates have been
higher. Patients who have been irradiated or sustained burns
will have an altered texture of bone that will reduce the capac­
ity to integrate implants.
Bone preparation
Meticulous, gentle surgical technique is vital for osseointegra­
tion to occur.10 Bone preparation must result in new bone
healing around the implant with no interposed fibrous tissue
formation and minimal bone necrosis (Fig. 31.9). Proper bone
healing results in bone ultimately being in intimate contact
with the titanium oxide layer. Sharp drill bits, copious saline
irrigation, and slower drilling speeds are required for success.
Studies have shown temperatures of 89°C occurring with high-
speed drilling despite cooling.38–40 Bone exposed to tempera­
tures greater than 47°C for 1 minute showed decreased new
bone formation. Exposure to 44°C showed no negative effect.
The fixture should only be handled by titanium instruments
and never touched by the gloved hand. It is further important
that the surgical field should be protected from fibers, powder,
and other substances that might hinder osseointegration. At
the junction of the titanium oxide and bone, a layer of ground
substance consisting of proteoglycans and glycosaminogly­
cans forms. The thickness of this layer is inversely related to the
strength of integration of the bone with the implant.
Traumatic surgery and an implant bed of low healing poten­
tial are said to be primary factors limiting successful osseointe­
gration. Implant mobility, overloading, and poor implant
biocompatibility are considered to be secondary factors in
failure of osseointegration. With successful osseointegration,
the weakest portion of the osseointegrated bone–implant
complex is the bone itself. After successful osseointegration,
attempting to remove an implant will result in failure within
the surrounding bone, not at the implant–bone interface.
Implant load
The load of the implant should preferably be in the longitu­
dinal direction. It is important to avoid rotational or cantilever

612
CHAPTER 31 • Facial prosthetics in plastic surgery
Fig. 31.10  (A,B) An ear template is used
to choose the appropriate site for implant
placement.
A
B
titanium is used by many specialties in many clinical situa­
tions, this application resulting in osseointegration should not
be confused with these other uses of titanium. Osseointegra­
tion biotechnology is very specific in terms of osseointegration
fixture production and preparation, surgical technique, and
final surgical result. Other implant systems (Conexão, Otorix,
Straumann, ITI, Southern) are available but are principally
based on the original implant.10
Compared to intraoral osseointegration, the fixtures for
extraoral use tend to be shorter (3–5 mm). The length of
implant used depends on the particular bone thickness.
Longer fixtures can sometimes be used in the frontal bone,
zygoma, and maxilla. Ideally bicortical purchase is obtained
if anatomically possible. The extraoral environment tends to
be a more hostile, less forgiving environment than the pro­
tected intraoral situation. The gingiva is constructed to have
mucosal penetration; saliva and the cleaning action of the
tongue are quite beneficial in keeping the abutments clean.
Penetration through skin with nearby hair, muscle, and seba­
ceous glands lends itself to the development of more soft-
tissue problems. The skin does not attach to the implant
abutment and is essentially maintained as an open wound.
The ability to modulate this interface better would result in
fewer local skin problems.
Surgery can be performed in one or two stages.1,12 The
one-stage procedure is usually reserved for adult patients
with good bone quality and quantity. The surgery can be
performed either under general anesthesia or with sedation
and local anesthesia.
A treatment template is used to locate the site for implant
placement. Appropriate implant positioning is crucial to the
ultimate prosthetic success. Digital technologies can be useful
for this aspect of treatment planning. Adobe Photoshop or
Geomagic Freeform have been used successfully for this
purpose (Fig. 31.10). In ear reconstruction, implants should be
placed under the future site of the antihelical fold of the ear
prosthesis. This is where there is maximal depth to hide the
protrusion of the fixture abutments within the prosthesis.
In orbital reconstruction, the implants need to be placed
well within the orbital rim rather than anteriorly, where it is
technically easier to place them. Again consideration needs to
be given to the space requirements of the orbital prosthesis in
all three dimensions. Within the orbit, the implant axes should
not align to a central converging point because this may make
prosthetic procedures very difficult.
In nasal reconstruction, better success is obtained by placing
implants into the floor of the nose rather than into the glabel­
lar region. In cases where there are concerns about the under­
lying bone quality or quantity, a radiological study will be
performed (Fig. 31.11). Simplant or Mimics software in com­
bination with a CT scan allows assessment of the bone and
surgical simulation of implant placement. Appropriate tem­
plates can then be constructed to help the surgeon with the
implant surgery.
At surgery the area is infiltrated with a lidocaine (Xylo­
caine) and epinephrine solution and a skin flap is elevated.
The periosteum is exposed and either a periosteal flap is
elevated or a circular opening made in the periosteum. A
surgical locating template is invaluable in difficult cases to
optimize positioning of the implant, minimize the extent of
surgical dissection, decrease the number of pilot drill holes
needed to find adequate bone, and decrease the duration of
the procedure. A 3.0-mm guide drill is used first. If bone is
present at this depth after drilling, the drill hole is deepened
to 4.0 mm. This drilling is carried out at a speed of 2000 rpm
with copious saline irrigation. The base of the guide hole is
checked to determine that penetration of underlying vital
structures has not occurred.
In the second step, the guide hole is widened with a coun­
tersink. A fresh countersink drill is used with copious saline
irrigation. This also prepares a flat countersink area on the
bony surface for seating of the implant flange. Flangeless fix­
tures are often placed in the orbital region. Issues with cleaning
and accumulation of debris around the implant flange can be
problematic and threaten long-term survival of the implant.
The third step involves placing the self-tapping implant. It
is placed at a drill speed of 15–20 rpm and 20–40 N-cm torque.
All these precautions are taken to minimize bone necrosis.
With bone necrosis, fibrous tissue will develop, compromising
the tissue–implant interface, and osseointegration will not
occur. All drills and countersinks are discarded after each
procedure. Craniofacial implants are 3.75 mm in diameter and
are available in 3.0, 4.0, and 5.5-mm lengths (Fig. 31.12). The
longest implant possible is preferable based on bone depth
and quality.
At the fourth step, a cover screw or space screw is placed in
the implant. This prevents soft-tissue ingrowth into the central
portion of the implant where the abutment will ultimately
connect. A space screw fits in the center of the implant and does
not increase the profile of the implant during the healing phase.

613
Prosthetic construction
are not as high as elsewhere. If an implant fails, then a sleeper
can be exteriorized, and the patient can continue to wear the
prosthesis with minimal interruption.
If a two-stage technique is needed phase II surgery involves
exposing the implant, radical thinning of the overlying and
surrounding tissue, creation of a hairless, nonmobile zone of
1.0 cm around each abutment, and connection of an abutment
to the underlying fixture. Improper soft-tissue surgery is the
most common cause of ongoing tissue reaction around the
abutment. Other surgical considerations include removal of
any residual soft-tissue elements to produce a flat tissue
surface for the auricular or nasal prosthesis. More recently
there has been success in the mastoid region with one-stage
placement of implants under optimal local conditions.54,55
Accepted clinical criteria for a one-stage procedure in the
mastoid region of older children (>10 years) or adults include:
■ no past history of irradiation
■ cortical layer of bone greater than 3.0 mm in thickness
■ uncomplicated surgery.
The technique is essentially the same as for phase I and II
surgery, but both phases are conducted at the same operation.
After one-stage surgery, the implant must be protected and
not loaded for at least 3 months.
Prosthetic construction
Construction of the prosthesis generally begins 4–6 weeks
after phase II surgery or 3–6 months after one-stage surgery
when local tissues have healed sufficiently to be a stable
base for overlying prosthetic construction. For auricular
prostheses a bar superstructure is individually designed and
connected to the abutments. Clips on the undersurface of the
prosthesis securely attach the prosthesis to the bar and are
most commonly used for ears. A magnetic retention system is
more commonly used for orbital prostheses and occasionally
for auricular prostheses when patient dexterity is limited. The
It is used if implants are placed under an area of existing skin
graft or thin skin flap, usually in the orbital region. The surgical
incisions are then closed if a two-stage procedure is planned.
If a one-stage procedure is possible, the outer layer of the
flap is elevated as an attached split-thickness graft, and
underlying soft tissues are removed. The edges around the
outside of the flap site are aggressively thinned and the graft
is replaced to take on the underlying periosteum. The most
common causes of future soft-tissue problems are related to
tissue movement around the abutment, and the remaining
hair follicles. In non-irradiated tissues, the implants are
usually left for approximately 3 months, at which time phase
II surgery can occur. In the midface or in patients with a
history of radiotherapy, this time period is usually extended
to 6–9 months. Usually, two implants are required for auricu­
lar reconstruction and at least three implants for orbital
reconstruction. Extra implants are often placed as sleepers in
the orbital region as the long-term success rates in this region
Fig. 31.11  (A,B) A Simplant or Mimics study can
be performed to determine quality and quantity of
underlying bone.
A
B
Fig. 31.12  Craniofacial implants and fixtures of commercially pure titanium.

614
CHAPTER 31 • Facial prosthetics in plastic surgery
prosthesis is first sculpted in wax and related to an acrylic
resin substructure containing retentive components. When
the prosthesis is anatomically acceptable, a mold is constructed
and the prosthesis is made from silicone elastomer.
Digital technologies have been helpful in prosthetic con­
struction.41 Capture of data from the “normal” side can be
done from a moulage or scan of the patient. With computer-
aided design software (Mimics, Magics, and Freeform), the
model is manipulated and the basic form of the prosthesis is
easily constructed using 3D printing (Fig. 31.13). This effi­
ciency optimizes the amount of time needed by the anaplas­
tologist with the patient. Constructing the prosthesis using
the anaplastologist’s time and skills efficiently is very impor­
tant, as they are in limited supply.
Another challenge to the prosthodontist and anaplastolo­
gist is color-matching based on the patient’s normal pigments
and extrinsic influences such as time of year and patient
occupation. One of the newer solutions includes the use of
spectrophotometry and computerized color formulation
technology for color-matching of the prosthesis to the patient.56
Patients will sometimes have summer and winter prostheses
to account for subtle pigmentary changes. Many small details
and techniques are used to add realism to the prosthesis.
Ideally, two prostheses are made at a time (Fig. 31.14). This
A
B
C
Fig. 31.13  (A–E) Digital technologies
were useful in prosthetic construction in
this orbital defect.
D
E
Fig. 31.14  Two prostheses are made at the same time with different coloration for
different seasons and to prevent a crisis if one prosthesis is lost or damaged. There
are clips on the undersurface of the prosthesis for secure attachment to the
implant-retained bar superstructure.

615
Craniofacial osseointegration outcomes
bone for implant placement into a region compromised by
surgery or radiation.
Craniofacial osseointegration outcomes
To evaluate the success of craniofacial osseointegration, several
parameters need to be studied.59,60 Success from a patient’s
perspective is the ability to use the prosthesis on a regular
basis and its positive effect on quality of life. This contributes
to psychological success as much as the aesthetic and func­
tional success. Assessment of outcomes must also include
individual implant success rates and local skin response.
Individual implant success rates
Jacobsson et al.18 proposed the following criteria for success of
a craniofacial osseointegrated implant:
1. The unattached implant should be immobile when
tested clinically.
2. Soft-tissue reactions around skin-penetrating abutments
should be type 0 (reaction-free) or type 1 (slight redness)
on the Holgers scale,61 not demanding treatment in
more than 95% of observations.
3. Individual implant performance should be characterized
by the absence of persistent and/or irreversible signs
and symptoms such as pain, infection, neuropathy, and
paresthesia.
4. A success rate of 95% in the mastoid process and 90% in
the orbital region in nonirradiated bone tissue at the
end of a 5-year observation period should be a
minimum criterion for success.
Many studies in the literature have documented implant
success rates. A 1992 study18 showed a success rate of 95% in
the mastoid and 72% in the orbital region. It was noted that
prevents a crisis situation if something happens to one of the
prostheses. A magnetic retention system is more commonly
used for orbital prostheses.
Maintenance program
The long-term success of osseointegration requires an effec­
tive ongoing maintenance regimen, analogous to the follow-up
in an organ transplantation program. Strong patient commit­
ment is required for success. In particular, conscientious care
of the periabutment area is crucial. This includes gentle clean­
ing on a daily basis, as well as diligent application of appro­
priately prescribed topical agents (Fig. 31.15) including
antibiotic ointment or topical steroid. Our protocol includes a
lifetime maintenance recall schedule to impress on them their
commitment, which is vital to long-term success. Maintenance
visits include assessing the periabutment region, measuring
soft-tissue height, checking for tissue reaction, and monitor­
ing the mechanical integrity of the implant–abutment assem­
bly. New prostheses are constructed as needed. The life of an
individual prosthesis can vary from 1 to 5 years depending
on extrinsic factors such as general care and exposure to
sunlight or cigarette smoke.6
Ancillary autogenous procedures
It is our belief that treatment of the patient’s craniofacial
defect is often best managed by a combination of osseointe­
gration and autogenous procedures to optimize the final
results (Box 31.5; Figs. 31.16 & 31.17).57,58 The goal of the ancil­
lary procedures may include decreasing the size of the facial
prosthesis, placing prosthetic margins at junctions of aesthetic
units, decreasing the size of the maxillary obturator, improv­
ing facial contour, improving symmetry, and bringing viable
Fig. 31.15  Requirements for care at abutment sites.
BOX 31.5  Ancillary soft-tissue procedures combined with
craniofacial osseointegration
Soft-tissue expanders
Scar revision
Free vascularized bone graft
Pedicled bone graft
Alar repositioning
Ectropion repair
Eyebrow reconstruction
Browlift
Static facial sling
Repositioning external auditory meatus
Onlay cartilage graft
Muscle flap
Bone contouring
Rhytidectomy
Tragal reconstruction