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

Suture
Nonabsorbable, monofilament suture (prolene or nylon) is used to perform anastomoses. Suture size
depends on vessel caliber and typically ranges from 8-0 to 11-0. Microneedles are 50 to 130 µm in
diameter with a sharp, tapered tip to pierce the tissue and a flat body to improve stability when held in
the needle driver.
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Automatic Suturing Devices
Anastomotic couplers are commonly used to simplify and expedite end-to-end venous anastomoses.
Patency rates are equivalent to hand-sewn anastomoses. 22 After matching the bushel size to the vessel
diameter, vessel ends are passed through a polyethylene ring, everted, and evenly secured on pins. Once
both donor and recipient vessels are prepared, the coupling device is used to approximate the vessel ends
and the rings are held together by interdigitating pins. The result is an automated anastomosis that is
stented open by a soft, plastic ring (Figure 5.2). This technique provides flexibility in tailoring the
anastomosis when vessel size mismatch is present by differential placement of the everted vessel wall on
the pins. Coupling devices may also be used on soft-walled arteries over 1 mm in diameter 23 but should
not be used on irradiated vessels.
FIGURE 5.2 Use of an anastomotic coupling device. A. With the device’s lateral wings open, each vessel is passed through a
plastic ring, and the vessel walls are everted and impaled on pins mounted on the rings. B. After both vessels are mounted, the
knob is turned to close the wings and secure the rings with the vessels in opposition. The rings are securely attached to each
other by the pins of one ring interlocking with the opposite plastic ring. After the anastomosis, the coupled rings are released in
the direction of the arrow by continuing to turn the knob.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
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Preoperative Planning
A multitude of flap options are available to the skilled microsurgeon. Donor site choice is dependent on
the size, location, and type of defect; the availability of recipient vessels; and functional needs of the
patient. Donor site morbidity should be considered and minimized.
Preoperative angiography (traditional or image-based) is sometimes required at the defect or donor site;
it is particularly helpful when physical examination findings are abnormal or if diseased or injured
vessels are suspected. When microsurgical reconstruction is needed for traumatic or infected wounds,
adequate debridement of the recipient site is required. Ideally, patients should be medically and
nutritionally optimized prior to free tissue transfer.
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Patient Considerations
It is essential to consider the patient’s general state of health and mindset when considering microsurgical
options. Patients must be fit enough to tolerate prolonged general anesthetic and willing to participate in
the lengthy recovery process. Active comorbidities, such as diabetes mellitus (DM), obesity, and nicotine
use, should be documented and optimized.
Age alone is not a contraindication for microsurgical reconstruction. Studies show that microsurgery can
be safely performed in children 24 and elderly patients 25 without an increase in flap failure or surgical
complications.
Macrovascular and microvascular diseases are known sequelae of diabetes; however, it is controversial as
to whether DM affects free flap outcomes. Animal models show poor intimal healing at the anastomotic
site and reduced venous patency, 26–28 but clinical studies show no difference in the rate of flap failure. 29
Strict perioperative glycemic control reduces overall surgical complications in diabetic patients.
Obesity is a known risk factor for flap and donor site complications. Free flaps in obese patients are twice
as likely to fail 30 ; however, the overall rate of flap failure is still very low, 31 especially when compared
with nonmicrosurgical alternatives (i.e., implant-based breast reconstruction). 32 The risks of seroma,
delayed wound healing, and mastectomy flap necrosis increase in obese patients. 30,33
Patients should be advised to quit smoking at least 4 weeks before surgery to reduce perioperative
complications. 34 Smoking impairs oxygenation, causes vasoconstriction, and introduces free radicals. 35,36
Studies indicate that smoking does not reduce anastomotic patency but does affect wound healing, skin
graft take over flaps, infection risk, flap necrosis, hernia formation, and length of hospital stay. 33,36,37
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Microsurgical Techniques
Surgical precision is the key factor in anastomotic patency. Ergonomic setup is the first step to success.
The surgeon should be seated or standing in a comfortable position with the shoulders and neck relaxed
and the forearms and wrists adequately supported. Ideally, the surgeon should position his or her body
parallel to the long axis of the vessel to allow for ergonomic intubation of the vessel lumen and forehand
suture placement. Wide surgical exposure is important; it may be necessary to extend the incision, further
mobilize recipient vessels, or reposition retractors to avoid operating in a hole.
Recipient vessels are prepared prior to division of the flap pedicle to minimize ischemia time. Adventitia
and periadventitial tissue is sharply excised to prevent it from becoming interposed between the donor
and recipient vessels, which is highly thrombogenic (Figure 5.3). Side branches are sealed with bipolar
electrocautery or micro clips. The vessels are then clamped, divided, and irrigated with heparinized
saline to remove intraluminal clot.
FIGURE 5.3 Donor and recipient vessel preparation. The excess adventitial tissue near the cut edge of the vessel is removed
with dissecting scissors to prevent intrusion into the lumen during the anastomosis. Care is taken to avoid excessive thinning,
which can result in vessel tears during the placement of sutures.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
The flap pedicle is likewise prepared and divided. Immediately after division, the flap is flushed through
with heparinized saline and transferred to the recipient site. It is positioned and secured in close
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proximity to the defect, paying careful attention to the pedicle to ensure that it is not twisted, kinked,
compressed, or under tension. Both donor and recipient arteries are dilated by inserting smooth-tipped
forceps into the lumen. Repeated dilation is avoided, as it weakens the vessel wall and causes vasospasm.
A forward-flow test is performed by releasing the clamp on the recipient artery to check inflow. This is
often done in replantation when vasospasm in injured vessels leads to the loss of the spurt sign in which
the blood flows intensely from the cut end of the vessel. The clamp is then replaced and the vessel end is
irrigated with heparinized saline. A double-opposing clamp is applied to approximate the donor and
recipient vessels. Vessels should be positioned for tension-free, intima-to-intima apposition (Figure 5.4).
Vascular grafts may be necessary if a tension-free anastomosis cannot be achieved.
FIGURE 5.4 Use of double-approximating microvascular clamps. The donor and recipient vessels are placed within the
clamps, and the vessel ends are approximated along the direction of the arrows. This technique maintains the correct
orientation of the vessels and facilitates suture placement. After the anterior suture line is complete, the clamps are turned over
to allow access to the posterior suture line.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
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Never start the anastomosis until you are satisfied with the setup.
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Anastomotic Technique
Variations on technique exist. Recent literature suggests no difference in patency rate based on suture
technique (simple interrupted versus continuous) 38 or anastomotic technique (end-to-end versus end-to-
side). 39 Surgeon preference and clinical scenario prevail.
Interrupted sutures are preferred when there is significant vessel size discrepancy. Continuous sutures
require less knot tying and are more time efficient. Continuous sutures have the added advantage of
equally distributing tension along the suture line, providing less opportunity for leakage. In practice,
interrupted sutures are commonly used for arterial anastomoses and continuous sutures for venous
anastomoses.
End-to-end anastomosis is appropriate for most arterial and venous anastomoses. End-to-side
anastomosis may be necessary in limb reconstruction to maintain distal perfusion, or when significant
size mismatch exists (Figure 5.5). End-to-side anastomoses are technically more difficult, evidenced by
longer mean ischemia times. 40
FIGURE 5.5 End-to-side anastomosis using continuous (running) sutures. An elliptical opening is created on the recipient
vessel wall, and the end of the donor vessel is anastomosed to this opening. The end-to-side technique maintains distal flow in
the recipient vessel and is frequently performed when there is a donor and recipient vessel diameter mismatch.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
Regardless of the anastomotic technique used, the following technical principles are critical:
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The needle should be held halfway along its length.
The most difficult sutures should be placed first.
Suture must enter the vessel perpendicular to the vessel wall and include all three layers of the wall
(Figure 5.6).
The distance from the cut end of the vessel to the needle entry point should be slightly greater than
the thickness of the vessel wall.
The tip of the needle should be visualized at all times within the vessel lumen.
Bisecting or trisecting sutures should be used for orientation (Figure 5.7).
Sutures should be placed equidistant from each other.
Between sutures, the needle should be placed within the visual field of the microscope to facilitate
retrieval for the next stitch.
The suture should not be tied if there is any concern that it has caught the back wall.
FIGURE 5.6 Forceps countertraction to facilitate needle placement and penetration. A. In select cases, partially open blunt
jeweler’s forceps tips are placed into the vessel lumen to evert the vessel wall, avoid inclusion of the back wall in sutures, and
provide countertraction for needle penetration. Extreme care must be taken to avoid traumatizing the vessel intima; some
microsurgeons avoid this technique for this reason. B. When the needle is passed from inside the vessel lumen to outside the
lumen, it is often useful to use the tips of the forceps to provide countertraction on the adventitial surface of the vessel to
facilitate needle penetration.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
FIGURE 5.7 Orientation sutures. A. Bisecting interrupted sutures are placed 180° apart, dividing the vessel circumference into
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half. This technique is particularly useful when there is a vessel size mismatch. B. Triangulating interrupted sutures are placed
120° apart, dividing the vessel circumference into thirds. This technique helps prevent inadvertent inclusion of the opposite wall
of the vessel in the remaining sutures; the surgeon applies gentle downward traction on the posterior orientation suture while
the other two sutures are gently retracted upward and laterally during placement of the remaining anastomotic sutures.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
Throughout the procedure and prior to placement of the last suture, the vessel lumen is irrigated with
heparinized saline. After completion of the both arterial and venous anastomoses, clamps are removed.
Venous clamps are removed first to restore outflow. The distal arterial clamp is then removed, backflow
is checked, and leaks are repaired. The proximal arterial clamp is removed last.
At this point, vessel handling should be limited. Topical lidocaine or papaverine and warm saline are
applied to reduce spasm. If bleeding occurs near the anastomotic site, the vessels are inspected for
unligated side branches, a second outflow vein from the flap, and leakage from the anastomosis itself.
After 3 to 5 minutes, the anastomoses are examined for patency. The artery should be pulsatile distal to
the anastomosis. Patent veins appear full and maroon in color. The flap is inspected for return of color
and bleeding from the edges. If doubt exists, a patency test (Figure 5.8) is performed as follows:
1. Jeweler’s forceps are used to gently occlude the vessel distal to the anastomosis.
2. A second pair of jeweler’s forceps is used to empty blood for several millimeters downstream.
3. The proximal forceps is then released while maintaining distal compression.
4. If patent, the empty segment fills with blood.
FIGURE 5.8 Use of the Acland test to confirm antegrade vascular flow through an anastomosis. A. The direction of blood flow
is indicated by the arrow. B. Two jeweler’s forceps are used to gently occlude the vessel distal to the venous anastomosis. C.
Blood is milked out of the vessel between the two forceps by gently sliding the distal forceps along the vessel without injuring it.
This results in a segment of collapsed vessel between the proximal and distal forceps. D. Releasing the proximal forceps allows
the collapsed vessel segment to be filled by antegrade flow if the anastomosis is patent. The distal forceps prevent retrograde
filling of the collapsed segment. This test should be performed sparingly to minimize potential trauma to the vessel intima.
Copyright held by, and used with permission of, The University of Texas M.D. Anderson Cancer Center.
This test is traumatic and should be performed only when necessary.
For nonflowing anastomoses, the artery and vein are inspected for twists, kinks, and points of
compression. The vessels are left alone for an additional 15 minutes. If the anastomosis is still not patent
or has thrombosed, the suture line is excised and the anastomosis redone. Excessive manipulation of
thrombosed vessels is avoided to prevent showering clot downstream. In the case of repeated thrombosis
despite a technically sound anastomosis, thrombolytic agents may be administered within the flap.
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Secondary Microsurgical Techniques
When it is not possible to perform tension-free, primary anastomosis of the donor and recipient vessels,
interposition grafts are used; this is often the case in replantation and extremity trauma when recipient
vessels must be outside the zone of injury. Autogenous vein grafts are readily available and are the most
common conduit used. They should be placed directionally for spanning vein gaps and reversed for
arterial gaps. The diameter of the graft should approximate that of the donor and recipient vessels—small
grafts are harvested from the volar wrist or forearm, and medium grafts from the dorsal foot. The
saphenous veins are often used when large-diameter vessels are required. Grafts should be harvested at
least 35% longer than the measured gap to accommodate for contraction; redundancy disappears with
time. 41 Long-term patency rates for vein grafts approach 100%, regardless of the length of the graft
required. 41 When used to bridge arterial gaps, histologic changes occur in vein grafts over time. A
neointima is formed by the ingrowth of smooth muscle cells from the recipient vessel, and the wall
thickens. 42
Arterial grafts are similarly reliable but less frequently used. Use of the radial, thoracodorsal, and
branches of the lateral femoral circumflex arteries has been described.
Synthetic grafts are not common in microsurgery. Animal models using fibrous polyurethane (PU) and
microporous polytetrafluoroethylene (PTFE) grafts show adequate early patency in high-flow, 43 short
segment conduits, but long-term anastomotic narrowing due to neointimal hyperplasia. 44 Significant
thrombosis and occlusion occur early in low-flow flaps. 45
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Microsurgery on Irradiated Vessels
Extreme care must be taken if the recipient vessels have been previously irradiated. Radiated vessels are
fragile, atherosclerotic, and fibrotic. It is difficult to recognize the junction between adventitia and media.
When the media is damaged during dissection, the vessel wall is weakened and at higher risk for leakage
and thrombosis. The intima is also more likely to be disrupted during vessel preparation, and sections
may lift away from the underlying media, which is highly thrombogenic. If any layer of the vessel wall is
injured, the vessel should be trimmed back proximal to the site of injury.
Evidence on the patency of microvascular anastomoses in irradiated tissue beds is conflicting; some
studies show higher rates of free flap failure, 46 whereas others show no effect on flap-related
complications. 47–49
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Anesthetic Considerations
Anesthesia is important in maximizing success in microsurgery. Basic intraoperative goals include
supporting circulatory volume, avoiding peripheral vasoconstriction, and maintaining normal body
temperature.
Adequate mean arterial pressure and cardiac output is required for flap perfusion. A combination of
crystalloid and colloid is appropriate for volume replacement with the goal of maintaining urine output
at 0.5 mL/kg/h. Adequate blood pressure promotes flap perfusion by increasing regional blood flow,
enhancing microvascular patency, and maintaining the fluidity of the blood in the microcirculation.
Anecdotally, vasopressors are avoided in microsurgery; however, multiple studies show no increase in
flap loss with intraoperative use of vasoactive medications. 50,51 Some studies even suggest that pressors
may be beneficial in microsurgery by increasing blood flow to skin flaps. 52 It is thought that the rise in
blood pressure overcomes any vasospastic effect of the medication. Adventitial stripping leads to
denervation of the donor and recipient vessels during dissection, further supporting this theory.
Temperature control during and after microsurgery is critical. Hypothermia causes vasoconstriction and
increases hematocrit and plasma viscosity because of erythrocyte and platelet clumping. Large body
surface areas may be exposed in microsurgical cases, making maintenance of temperature difficult.
Patients can be warmed by forced-air blankets, warmed IV fluids, humidified and warmed anesthetic
gases, and increased ambient room temperature.
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Postoperative Management
Postoperatively, efforts are made to offload pressure from flap and prevent vasospasm. Dressings are
minimized so that the whole flap is easily evaluated. Circumferential dressings and ties are avoided.
Patients are positioned to prevent direct pressure on the flap; this may include application of an external
fixator for extremity reconstruction. The room is warmed. Fluids are managed to maintain adequate urine
output and systolic blood pressure and keep hematocrit at 25% to 35%. Pain control is optimized.
Caffeine and nicotine are prohibited.
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Antithrombotics
The routine use of antithrombotic agents in the postoperative period remains controversial. Multiple
studies show that postoperative antithrombotic use of any type offers no protection from microvascular
thrombosis and increases complication rates. 12,13 However, in a recent survey, 84% of surgeons who
routinely perform lower extremity reconstruction reported using at least one form of antithrombotic
before, during, or after surgery. 53 The most common antithrombotic agents used in routine postoperative
care are aspirin and heparin. Further investigation is required.
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Postoperative Monitoring
Thrombosis is most common within 24 hours of surgery. Early failure is often related to anastomotic
imperfections or pedicle positioning. If a problem is detected early, the flap can be salvaged by
exploration and revision of the anastomosis. The success rate of flap salvage is inversely related to the
time interval from the onset of ischemia to restoration of blood flow. Prompt recognition and timely
intervention is required. Overall, approximately 50% of ailing free flaps can be salvaged. 8
Clinical evaluation is standard for flap monitoring. Color, capillary refill, turgor, and temperature are
evaluated. A flap without inflow will be cool, be pale, and lack capillary refill. Rapid capillary refill,
swelling, or purple discoloration may indicate venous thrombosis.
Many adjuncts to clinical evaluation exist. Hand-held Doppler ultrasound is commonly used to monitor
both arterial and venous waveforms. Perforators to the skin are identified intraoperatively, and their
location is marked with a fine suture on the skin surface for future localization. Implantable, ultrasonic
Doppler probes can be used for flaps without a skin paddle or completely buried flaps. Surface
temperature measurements and pulsoximetry are helpful in digital replantation. Other monitoring
systems include transcutaneous oxygen tension, near-infrared spectroscopy, intravenous fluorescein
angiography, pH measurement, interstitial fluid pressure, and reflection plethysmography. There is no
consensus on which method is most effective.
Regardless of the monitoring technique, flap checks should be performed by an experienced observer at
least once every hour for the first 48 hours following surgery. After 48 hours, flap monitoring is spaced
out to every 2 hours until postoperative day 5 and then decreased to every 4 hours until discharge. The
rate of successful flap salvage is highest in the early postoperative course. 8
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Management of the Ailing Free Flap
At the first sign of a problem, the flap and patient are inspected to detect any easily correctable issues—
patient positioning, flap dependency, constrictive dressings, etc. Flap inset sutures are released if external
pedicle compression is suspected. The threshold to return to the operative room is low. Exploration
should proceed immediately if there is any clinical suspicion for thrombosis. Doppler signals may persist
for several hours despite venous thrombosis.
During a take-back procedure, the flap is elevated and the anastomosis inspected. Intravenous heparin
(5000 units) is administered and the anastomosis is taken down. If clot is present, mechanical
thrombectomy is performed with a Fogarty catheter. The goal is to remove the thrombus in its entirety—
residual clot may be a nidus for additional thrombus or the source of microemboli. Both the donor and
recipient vessels are trimmed back to pristine intima. Vein grafts may be required if primary anastomosis
cannot be performed without tension. A thrombolytic agent (streptokinase, urokinase, or tissue
plasminogen activator) is infused while the flap is occluded from systemic circulation. If there is no
longer inflow from the recipient vessels, a different recipient site is chosen.
There is no indication for routine anticoagulation when conditions are optimal; however, in the case of
postoperative thrombosis, intraoperative, local fibrinolytic therapy and postoperative anticoagulation
may be indicated in situations where mechanical and vascular factors are unfavorable.
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Leeches
Leeches are a useful adjunct for flaps with signs of venous congestion despite a patent venous
anastomosis. They are only indicated when a flap has good inflow but limited drainage, and should not
replace reexploration of the venous anastomosis if patency is in question. Leeches are applied directly to
the flap. They consume several milliliters of blood at each meal and fall off at satiety. Prophylaxis against
Aeromonas hydrophila is necessary because this organism routinely inhabits the digestive tract of leeches.
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Flap Failure
Salvage attempts are abandoned when there is no return of perfusion after reexploration. Tissue type and
warm ischemia time are also considered. Obviously necrotic flaps should be debrided promptly to reduce
inflammation. After removal of a failed free flap, dressings or skin grafts can be used to temporize a
wound. Local or regional flap options or a second free flap may be considered.
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Applications of Microsurgery
Free Tissue Transfer
Free flaps are used to close wounds and restore form and function in patients with traumatic, oncologic,
or congenital defects. Multiple types of flaps exist and selection is based on the type of defect and the
goals of reconstruction.
Muscle flaps are useful when bulk is required or a dead space exists. A skin paddle may be included
depending on the contour requirements of the defect, or a skin graft may be placed over the bare muscle.
Functional free muscle transfer is also possible; it involves transfer of a muscle with microvascular
anastomosis and microsurgical reinnervation at the recipient site.
Skin and fascia flaps can be derived from any perforating blood vessel using the angiosome concept.
These flaps provide versatile, thin, well-vascularized soft tissue coverage. If desired, bulk may be
provided by including subcutaneous tissue. Donor site morbidity is minimal because muscle is spared.
Fascia-only flaps have the added advantage of providing a gliding surface for tendon reconstruction.
Osseous flaps are used less frequently than soft tissue flaps but are helpful to reconstruct bony defects of
the mandible, midface, and extremities. Vascularized bone autografts are superior to nonvascularized
bone graft in defects over 5 centimeters in regard to early incorporation, bone hypertrophy, mechanical
strength, and osseous mass retention. 54
Microvascular transfer of bowel segments (proximal jejunum or colon) is used to reconstruct the oral
cavity, pharynx, and esophagus. The greater omentum is an excellent source of well-vascularized tissue.
It is commonly used for sternal and scalp reconstruction. Laparoscopic harvest is possible.
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Nerve Repair
Peripheral nerves have some capacity to regenerate after injury; however, poor functional results are
common. Microsurgical techniques are required to optimize outcomes. Microdissection, identification
and resection of injured nerve segments, fascicular matching, and tension-free epineurial or grouped
fascicular repair are prudent. Recent advances in nerve surgery include end-to-side repairs and nerve
transfers. In an end-to-side repair, the distal end of an injured nerve is coapted to the side of an uninjured
donor nerve. Nerve transfers use redundant or unimportant fascicles from a donor nerve to innervate
critical motor or sensory branches close to their target end organ. Techniques such as these improve
functional results and reduce morbidity after peripheral nerve injury.
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Lymphatic Surgery
Refinements in magnification, equipment, and technique have revolutionized the treatment of
lymphedema. Lymphatic surgery is an exciting application of supermicrosurgery, defined as the
anastomosis of structures less than 0.5 mm in diameter. Vascularized lymph node transfer and
lymphaticovenous bypass offer physiologic solutions for restoration of lymphatic flow.
Vascularized lymph node transfer involves transplanting functioning lymph nodes to an area affected by
lymphedema. Donor sites include supraclavicular, submental, groin, or gastroepiploic nodes. The exact
mechanism of action in vascularized lymph node transfer is unknown; however, two theories exist: (1)
transplanted lymph nodes provide growth factors that induce lymphangiogenesis in the affected limb;
and (2) transplanted lymph nodes act as a lymphatic pump, driven by high-pressure arterial inflow and
low-pressure venous outflow.
In lymphaticovenous bypass, obstructed lymphatic channels are identified and their flow is redirected
into a nearby low-pressure venule. Restoration of unimpeded flow reduces lymphedema severity,
particularly in patients with early-stage upper extremity disease.
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Replantation
Microsurgical techniques are used to primarily repair amputations of extremities, genitalia, and facial
structures. Replantation is most successful in patients who sustain sharp injuries and seek medical
attention immediately. Crush or avulsion-type mechanisms cause a significant zone of injury and
replantation is less likely to succeed. Patients with segmental or multilevel injuries are also poor replant
candidates. When successful, replantation can help patients avoid disabling or disfiguring defects and
complex, multistage reconstructive procedures.
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Conclusion
Microsurgical techniques have forever changed the face of plastic surgery. Modern microsurgery has
progressed far beyond the simple tenet of keeping a vessel patent. Refined techniques focus on
maximizing function, restoring near-normal form, and minimizing donor site morbidity.
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Acknowledgment
The work was supported by a Midcareer Investigator Award in Patient-Oriented Research (2 K24-
AR053120-06) to Kevin C. Chung. The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of Health.
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Questions
1. Which of the following conditions is a risk factor for free flap failure?
a. Age less than 18 years
b. Age greater than 65 years
c. Active nicotine use
d. Obesity
e. DM
2. Which of the following is a proven benefit of using a coupler device?
a. Decreased anastomosis time
b. Improved anastomotic patency
c. Increased intima-to-intima apposition
d. Reduced cost
e. Decreased vessel kinking
3. A 23-year-old man with a traumatic wound involving the distal third of the leg is scheduled to
undergo soft-tissue reconstruction with an anterolateral thigh free flap. Which of the following is
most likely to have the greatest effect on anastomotic patency?
a. Anastomotic technique
b. Magnification type
c. Surgical precision
d. Antithrombotic use
e. Suture technique
4. A 62-year-old woman with invasive ductal carcinoma undergoes mastectomy and reconstruction
with a deep inferior epigastric artery free flap. Intraoperatively, the patient experiences hypotension
and norepinephrine is administered. Which of the following is the most likely effect of this treatment
on the outcome of the flap?
a. Microvascular thrombosis
b. Partial flap loss
c. Delayed wound healing
d. Fat necrosis
e. No effect
5. Systemic dextran administration is associated with which of the following effects?
a. Improved anastomotic patency
b. Protection from ischemia reperfusion injury
c. Neutropenia
d. Hypokalemia
e. Increased systemic complications
6. A 73-year-old man undergoes resection of an 8 × 10 cm invasive squamous cell carcinoma of the
scalp and immediate reconstruction with a radial forearm free flap. Flap monitoring is planned.
Vascular compromise is most likely to occur during which of the following postoperative time
periods?
a. 0 to 1 days
b. 2 to 3 days
c. 4 to 5 days
d. 6 to 7 days
e. 8 to 9 days
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7. A 43-year-old woman is evaluated 6 hours after undergoing delayed breast reconstruction with
profunda artery perforator flaps. Arterial signals are present bilaterally on Doppler examination.
Capillary refill time is 3 seconds on the right and 1 second on the left. The left flap appears mottled
and darker in color compared with the right side. Which of the following is the most appropriate
management of the left breast?
a. Observation
b. Administration of systemic heparin
c. Application of nitroglycerin paste
d. Application of leeches
e. Return to the operating room
8. A 46-year-old women undergoes bilateral breast reconstruction using deep inferior epigastric
artery free flaps. On evaluation of the flaps 6 hours later, the right breast appears mottled and
engorged. Administration of which of the following is contraindicated in this patient?
a. Thrombolytics to the flap vessels
b. Systemic thrombolytics
c. Heparinized saline irrigation to the flap vessels
d. Systemic heparin
e. Papaverine to the flap vessels
9. A 17-year-old girl is evaluated 18 hours after undergoing soft-tissue coverage of Gustilo Grade III
distal tibia fracture with a latissimus dorsi free flap. The flap appears dark and swollen and Doppler
signals are absent. On reexploration in the operating room, thrombus is noted within the artery and
vein. Which of the following is the most appropriate treatment to salvage this flap?
a. Aspirin
b. Heparinized saline to flap vessels
c. Systemic dextran
d. Systemic thrombolytic
e. Mechanical thrombectomy
1. Answer: d. Age is not a contraindication for microsurgical reconstruction. Microsurgery can be
safely performed in children and elderly patients without an increase in flap failure.
Patients should be advised to quit smoking at least 4 weeks before surgery to reduce perioperative
complications. Smoking does not reduce anastomotic patency but does affect wound healing, skin
graft take over flaps, infection risk, flap necrosis, hernia formation, and length of hospital stay.
Vascular disease is a known sequela of diabetes; however, studies show no difference in the rate of
flap failure in diabetic patients. Obesity is a known risk factor for flap and donor site complications.
Free flaps in obese patients are twice as likely to fail.
2. Answer: a. Anastomotic couplers expedite end-to-end venous anastomoses. Patency rates are
equivalent to hand-sewn anastomoses. The other options have not been proven as benefits of a
coupler device over other techniques.
3. Answer: c. Surgical precision is the key factor in anastomotic patency. Magnification in the form of
surgical loupes or an operating microscope is acceptable. Studies show equal patency rates in vessels
over 1 mm in diameter. Postoperative antithrombotic use offers no protection from microvascular
thrombosis and increases complication rates. There is no difference in patency rate based on suture
technique (simple interrupted versus continuous) or anastomotic technique (end-to-end versus end-
to-side).
4. Answer: e. Vasopressors are typically avoided in microsurgery because of the concern that
vasospasm of the anastomosis will result in thrombosis. Volume resuscitation is the first-line
treatment for hypotension, when possible. Despite this, multiple studies show that intraoperative use
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of vasoactive agents has no effect on postoperative flap outcomes.
5. Answer: e. Dextran is an antithrombotic agent sometimes used in microsurgical procedures. It
decreases red blood cell aggregation through both antiplatelet and antifibrin effects. Dextran has no
effect on flap survival but a 3.9- to 7.2-fold increase in systemic complications including renal failure,
pulmonary edema, and congestive heart failure. Protection from ischemia reperfusion injury,
neutropenia, and hypokalemia are not associated with dextran.
6. Answer: a. Thrombosis is most common within 24 hours of surgery. Early failure is often related to
anastomotic imperfections or pedicle positioning. If a problem is detected early, the flap can be
salvaged by exploration and revision of the anastomosis. Vascular thrombosis can occur at later
times, but such events are generally infrequent.
7. Answer: e. The left flap shows signs of venous insufficiency—brisk capillary refill, mottled and
dark appearance. Doppler signals may persist for several hours despite venous thrombosis. The most
appropriate management is emergent reexploration. If a problem is detected early, the flap can be
salvaged by revision of the anastomosis. The success rate of flap salvage is inversely related to the
time interval from the onset of ischemia to restoration of blood flow. Observation is unacceptable.
Systemic heparin may prevent further clot formation but will not dissolve acute clot or resolve
pedicle kinking. Nitroglycerin paste can improve venous congestion in pedicled flaps but does not
obviate the need for reexploration in a microsurgical flap. Application of leeches will drain excess
blood from the flap but will not address the underlying problem.
8. Answer: b. Heparin may be used locally or systemically during flap salvage to irrigate existing
thrombus and discourage clot propagation. Topical papaverine is routinely applied to flap vessels to
reduce spasm. Thrombolytic agents, such as tissue plasminogen activator (tPA) or streptokinase, may
be used within the flap but should not be administered systemically.
9. Answer: e. The most important treatment in this patient is mechanical thrombectomy of the flap
artery and vein, which reduces clot burden and may restore flow. Intraflap tPA is also commonly
used during flap salvage to dissolve microthrombi.
Systemic thrombolytic administration carries a high risk of distant complications and is unlikely to
dissolve clot within the flap. Administration of intraflap heparin will prevent further clot formation
but will not dissolve the clot in the flap pedicle. Dextran has mild thrombolytic properties but it is
not as effective as tPA in lysing clot within the flap and carries a high risk of systemic complications.
Aspirin has no thrombolytic properties and has a slow onset of action.
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References
Jassinowski, A. Die Artiennhat: eine experimentelle Studie. Inaug Diss Dorpat. 1889.
Carrel, A. La technique operatoire des anastomoses vasculaires et la transplantation des visceres. Lyon Med. 1902;98:859-863.
Hopfner, E. Uber Gefassnhaht, Gefasstransplantationen und Replantation von amputierten Extremitaten. Arch Klin Chir. 1903;70:417-471.
Nylen, CO. The microscope in aural surgery: its first use and later development. Acta Otolaryngol Suppl. 1954;116:226-240.
Holmgren, G. Some experiences in surgery of otosclerosis. Acta Otolaryngol. 1923;5:460-466.
Jacobson, JH, Suarez, EL. Microsurgery in the anastomosis of small vessels. Surg Forum. 1960;11:243-245.
Tamai, S. History of microsurgery. Plast Reconstr Surg. 2009;124(suppl 6):e282-e294.
Mirzabeigi, MN, Wang, T, Kovach, SJ, et al. Free flap take-back following postoperative microvascular compromise: predicting salvage
versus failure. Plast Reconstr Surg. 2012;130(3):579-589.This article provides recent data on microsurgical success rates from a high-volume center.
Harashina, T, Fujino, T, Watanabe, S. The intimal healing of microvascular anastomoses. Plast Reconstr Surg. 1976;58(5):608-613.
Hayhurst, JW, O’Brien, BM. An experimental study of microvascular technique, patency rates and related factors. Br J Plast Surg.
1975;28(2):128-132.
Chang, WH, Petry, JJ. Platelets, prostaglandins, and patency in microvascular surgery. J Microsurg. 1980;2(1):27-35.
Lighthall, JG, Cain, R, Ghanem, TA, Wax, MK. Effect of postoperative aspirin on outcomes in microvascular free tissue transfer surgery.
Otolaryngol Head Neck Surg. 2013;148(1):40-46.This article reviews a large case series of patients treated with various combinations of antithrombotic
agents and concludes that postoperative thromboprophylaxis with aspirin does not increase the odds of flap survival and may be associated with a higher
complication rate.
Disa, JJ, Polvora, VP, Pusic, AL, et al. Dextran-related complications in head and neck microsurgery: do the benefits outweigh the risks? A
prospective randomized analysis. Plast Reconstr Surg. 2003;112(6):1534-1539.This study evaluates morbidity associated with dextran
administration in head and neck microsurgery patients and concludes that there is no effect on overall flap survival and a significantly increased risk of
systemic complications.
Serafin, D, Lesesne, CB, Mullen, RY, Georgiade, NG. Transcutaneous PO2 monitoring for assessing viability and predicting survival of skin
flaps: experimental and clinical correlations. J Microsurg. 1981;2(3):165-178.
Eriksson, E, Anderson, WA, Replogle, RL. Effects of prolonged ischemia on muscle microcirculation in the cat. Surg Forum. 1974;25(0):254-
255.
Berggren, A, Weiland, AJ, Dorfman, H. The effect of prolonged ischemia time on osteocyte and osteoblast survival in composite bone grafts
revascularized by microvascular anastomoses. Plast Reconstr Surg. 1982;69(2):290-298.
Cooley, BC, Hansen, FC, Dellon, AL. The effect of temperature on tolerance to ischemia in experimental free flaps. J Microsurg. 1981;3(1):11-
14.
May, JW, Chait, LA, O’Brien, BM, Hurley, JV. The no-reflow phenomenon in experimental free flaps. Plast Reconstr Surg. 1978;61(2):256-267.
Ross, DA, Ariyan, S, Restifo, R, Sasaki, CT. Use of the operating microscope and loupes for head and neck free microvascular tissue transfer:
a retrospective comparison. Arch Otolaryngol Head Neck Surg. 2003;129(2):189-193.
Pannucci, CJ, Kovach, SJ, Cuker, A. Microsurgery and the hypercoagulable state: a hematologist’s perspective. Plast Reconstr Surg.
2015;136(4):545e-552e.
Shenaq, SM, Klebuc, MJ, Vargo, D. Free-tissue transfer with the aid of loupe magnification: experience with 251 procedures. Plast Reconstr
Surg. 1995;95(2):261-269.
Cope, C, Lee, K, Stern, H, Pennington, D. Use of the vascular closure staple clip applier for microvascular anastomosis in free-flap surgery.
Plast Reconstr Surg. 2000;106(1):107-110.
Spector, JA, Draper, LB, Levine, JP, Ahn, CY. A technique for atraumatic microvascular arterial coupling. Plast Reconstr Surg.
2007;119(6):1968-1969.
Momeni, A, Lanni, M, Levin, LS, Kovach, SJ. Microsurgical reconstruction of traumatic lower extremity defects in the pediatric population.
Plast Reconstr Surg. 2017;139(4):998-1004.
Serletti, JM, Higgins, JP, Moran, S, Orlando, GS. Factors affecting outcome in free-tissue transfer in the elderly. Plast Reconstr Surg.
2000;106(1):66-70.
Barr, LC, Joyce, AD. Microvascular anastomoses in diabetes: an experimental study. Br J Plast Surg. 1989;42(1):50-53.
Cooley, BC, Hanel, DP, Anderson, RB, et al. The influence of diabetes on free flap transfer: I. Flap survival and microvascular healing. Ann
Plast Surg. 1992;29(1):58-64.
Colen, LB, Stevenson, A, Sidorov, V, et al. Microvascular anastomotic thrombosis in experimental diabetes mellitus. Plast Reconstr Surg.
1997;99(1):156-162.
Miller, RB, Reece, G, Kroll, SS, et al. Microvascular breast reconstruction in the diabetic patient. Plast Reconstr Surg. 2007;119(1):38-45.
Kroll, SS. Necrosis of abdominoplasty and other secondary flaps after TRAM flap breast reconstruction. Plast Reconstr Surg. 1994;94(5):637-
643.
Seidenstuecker, K, Munder, B, Mahajan, AL, et al. Morbidity of microsurgical breast reconstruction in patients with comorbid conditions.
Plast Reconstr Surg. 2011;127(3):1086-1092.
Garvey, PB, Villa, MT, Rozanski, AT, et al. The advantages of free abdominal-based flaps over implants for breast reconstruction in obese
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patients. Plast Reconstr Surg. 2012;130(5):991-1000.
Selber, JC, Kurichi, JE, Vega, SJ, et al. Risk factors and complications in free TRAM flap breast reconstruction. Ann Plast Surg. 2006;56(5):492-
497.
Rohrich, RJ. Cosmetic surgery and patients who smoke: should we operate? Plast Reconstr Surg. 2000;106(1):137-138.
Kaufman, T, Eichenlaub, EH, Levin, M, et al. Tobacco smoking: impairment of experimental flap survival. Ann Plast Surg. 1984;13(6):468-472.
Chang, LD, Buncke, G, Slezak, S, Buncke, HJ. Cigarette smoking, plastic surgery, and microsurgery. J Reconstr Microsurg. 1996;12(7):467-474.
Spear, SL, Ducic, I, Cuoco, F, Hannan, C. The effect of smoking on flap and donor-site complications in pedicled TRAM breast
reconstruction. Plast Reconstr Surg. 2005;116(7):1873-1880.
Alghoul, MS, Gordon, CR, Yetman, R, et al. From simple interrupted to complex spiral: a systematic review of various suture techniques for
microvascular anastomoses. Microsurgery. 2011;31(1):72-80.
Tsai, YT, Lin, TS. The suitability of end-to-side microvascular anastomosis in free flap transfer for limb reconstruction. Ann Plast Surg.
2012;68(2):171-174.
Apostolides, JG, Magarakis, M, Rosson, GD. Preserving the internal mammary artery: end-to-side microvascular arterial anastomosis for
DIEP and SIEA flap breast reconstruction. Plast Reconstr Surg. 2011;128(4):225e-232e.
Mitchell, GM, Zeeman, BJ, Rogers, IW, et al. The long-term fate of microvenous autografts. Plast Reconstr Surg. 1988;82(3):473-479.
Biemer, E, Holzmann, T, Wriedt-Lubbe, I, et al. Autologous vein grafts as artery replacement in microsurgery. An experimental study of
micro- and macromorphologic changes 3 weeks to 12 months postoperatively. Handchirurgie. 1981;13(1-2):108-113.
van der Lei, B, Wildevuur, CR. Microvascular polytetrafluoroethylene prostheses: the cellular events of healing and prostacyclin production.
Plast Reconstr Surg. 1988;81(5):735-741.
Hess, F, Jerusalem, C, Braun, B, Grande, P. Evaluation of the patency rate of fibrous microvascular polyurethane prostheses after
implantation in the rat aorta. Microsurgery. 1983;4(3):178-181.
Shen, TY, Mitchell, GM, Morrison, WA, O’Brien, BM. The use of long synthetic microvascular grafts to vascularise free flaps in rabbits. Br J
Plast Surg. 1988;41(3):305-312.
Khouri, RK, Cooley, BC, Kunselman, AR, et al. A prospective study of microvascular free-flap surgery and outcome. Plast Reconstr Surg.
1998;102(3):711-721.This study reviews outcomes from a large group of microsurgeons and concludes that reconstruction of an irradiated recipient site
and the use of a skin-grafted muscle flap were the only statistically significant predictors of flap failure. Flap recipient site, indication for surgery,
patient factors, anastomosis technique, and thromboprophylaxis did not have a significant effect on flap outcome.
Kroll, SS, Schusterman, MA, Reece, GP, et al. Choice of flap and incidence of free flap success. Plast Reconstr Surg. 1996;98(3):459-463.
Shaari, CM, Buchbinder, D, Costantino, PD, et al. Complications of microvascular head and neck surgery in the elderly. Arch Otolaryngol
Head Neck Surg. 1998;124(4):407-411.
Chow, WB, Rosenthal, RA, Merkow, RP, et al. Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline
from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. J Am Coll
Surg. 2012;215(4):453-466.
Chen, C, Nguyen, MD, Bar-Meir, E, et al. Effects of vasopressor administration on the outcomes of microsurgical breast reconstruction. Ann
Plast Surg. 2010;65(1):28-31.
Harris, L, Goldstein, D, Hofer, S, Gilbert, R. Impact of vasopressors on outcomes in head and neck free tissue transfer. Microsurgery.
2012;32(1):15-19.This study reviews intraoperative vasopressor administration during microsurgical cases and concludes that they are frequently used
and do not adversely affect flap outcomes.
Cordeiro, PG, Santamaria, E, Hu, QY, Heerdt, P. Effects of vasoactive medications on the blood flow of island musculocutaneous flaps in
swine. Ann Plast Surg. 1997;39(5):524-531.
Xipoleas, G, Levine, E, Silver, L, et al. A survey of microvascular protocols for lower-extremity free tissue transfer I: perioperative
anticoagulation. Ann Plast Surg. 2007;59(3):311-315.
Weiland, AJ, Phillips, TW, Randolph, MA. Bone grafts: a radiologic, histologic, and biomechanical model comparing autografts, allografts,
and free vascularized bone grafts. Plast Reconstr Surg. 1984;74(3):368-379.
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C H A P T E R 6
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Concepts of Skin Grafts and Skin Substitutes
Sabrina N. Pavri and Henry C. Hsia
Key Points
Split-thickness skin grafts contain epidermis and a portion of underlying dermis, whereas full-
thickness skin grafts contain epidermis and the entire dermis.
Split-thickness skin grafts, when compared with full-thickness skin grafts, experience less primary
contracture, more secondary contracture, may experience more pigment changes, be more
susceptible to trauma, and have a lower metabolic demand of the recipient site wound bed.
Skin grafts heal by a process of imbibition and revascularization through angiogenesis. Graft healing
is associated with swelling of the graft, increased mitotic activity leading to desquamation, and
eventual reepithelialization over a span of about 4 weeks.
Common causes of graft failure include hematoma, infection, seroma, shear forces, and a poorly
vascularized wound bed.
Skin substitutes come in a variety of forms and can be considered as biologic dressings that provide
clinicians more options in complex wound management, either as an alternative to traditional
dressings or as a bridge to more definitive treatment such as surgical closure.
Providing wound coverage for a patient through the application and grafting of skin harvested from a
distinct or separate region located elsewhere on that patient’s body is a key foundational technique in the
armamentarium of the plastic surgeon. Skin grafting originated in India approximately 3000 years ago,
where full-thickness grafts comprising the entire dermis and epidermis layers of the skin harvested from
the gluteal region were used by the Koomes tilemaker caste for nasal reconstruction after amputation, a
common punishment for criminals. 1 The knowledge of this surgical technique did not make its way into
Western medicine until the early 19th century. In 1817, Sir Astley Cooper used a full-thickness skin graft
from a man’s amputated thumb to provide coverage for the remaining stump. This was followed by a
successful nasal reconstruction using a skin graft, performed by Buenger in 1823.
However, because of the difficulties his European contemporaries encountered while attempting to
replicate his technique, skin grafting did not become widely popular until 1869, when Reverdin
published his landmark paper reporting successful pinch grafts. Thin split-thickness grafts were
popularized in the late 19th century by Ollier (1871) and Thiersch (1874), as a method to cover defects
with a large surface area, becoming known as Ollier-Thiersch grafts. However, the drawbacks of these
grafts quickly became evident, with several reports in the 1890s detailing the subsequent wound
contractures and graft susceptibility to trauma. During the same period, surgeons and ophthalmologists
were using full-thickness skin grafts to correct cases of ectropion. The technique of full-thickness skin
grafting was published by Wolfe in 1874 and popularized by Krause, with full-thickness skin grafts
becoming known as Wolfe-Krause grafts. 2,3
Despite the development of more advanced surgical techniques, autologous skin grafting remains a
mainstay of wound coverage reconstruction, especially for burn trauma. However, the relative lack of
donor site availability in patients with extensive burns and the suboptimal aesthetic and functional
outcomes commonly associated with autologous skin grafts drive a search for alternatives and led to the
development of skin substitutes in recent decades. Although initially intended for primary coverage, skin
substitutes have been found to have a salutary impact on wounds even when they fail as permanent
wound coverage options. In contemporary applications, skin substitutes have been used more commonly
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as biologic dressings and bridging therapies to eventual definitive closure via autologous skin grafts or
other conventional plastic surgical techniques. Nonetheless, much ongoing work continues in efforts to
develop an alternative to autologous skin grafts that would promote regenerative healing of wounds in a
definitive fashion.
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Anatomy of Skin Grafts
The skin is the largest organ in the body, accounting for 15% of total adult body weight, with a layered
structure (Figure 6.1) that assists in its functions of protection, sensation, thermoregulation, control of
evaporation, and absorption. 4 The epidermis, or the outermost layer of the skin, is of ectodermal origin;
and its cells undergo continuous differentiation, migration, and eventual shedding. 90% to 95% of
epidermal cells are keratinocytes, with the remainder including Langerhans cells, melanocytes, and
Merkel cells. The epidermis is substratified into five layers (from superficial to deep)—stratum corneum,
stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. The epidermis has an
average thickness of 100 µm, but this can range widely, from 50 µm on the eyelids to 1 mm on the
glabrous skin of the hands and feet.
FIGURE 6.1 The anatomy of autologous skin grafts. Human skin is a layered structure comprised of several elements. Split-
thickness skin grafts include the epidermis and the superficial portion of the dermis, whereas full-thickness skin grafts include
the epidermis and the entire dermis layers.
The dermis is a structure of mesodermal origin comprised of collagen and elastin fibers, ground
substance, and the deeper portions of the epithelial appendages (eccrine and apocrine sweat glands, and
pilosebaceous follicles). Although fibroblasts are the dominant cell type in the dermis, it also contains
mesenchymal dermal dendrocytes and mast cells. The papillary dermis is the thin uppermost layer of the
dermis composed of loosely arranged collagen fibers, which contains a capillary network that provides
nutrients to the epidermis and acts as a mechanism of heat exchange and regulation. The reticular dermis
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lies below the papillary dermis and is composed of dense irregular collagen fibers. It also contains most of
the dermal elastin, as well as the pilosebaceous units and sweat glands.
Within the dermis layer, there exist two horizontal plexuses of vessels connected by bridging vessels that
traverse the dermis vertically. The superficial plexus lies at the interface of the papillary and reticular
dermis, whereas the deep plexus lies adjacent to the deep border of the dermis. These plexuses are closely
associated with nerve bundles and structures that help mediate sensations such as pain, temperature,
itch, touch, and pressure. Below the dermis lies the hypodermis or subcutis, which is composed of
adipocytes separated by fibrous septa containing fibroblasts, dendrocytes, and mast cells, and into which
extend the deepest parts of the epithelial appendages, as well as vessels and nerves that contribute to the
overlying dermal plexuses. In structural continuity with the underlying subcutaneous fat, this layer
provides thermoregulation, insulation, energy, and mechanical protection for the skin.
Split-thickness skin grafts are defined as grafts involving the epidermis and any part of the dermis, and
range in thickness from approximately 0.005 to 0.030 inches. They are classified as thin (0.005–0.012
inches), medium (0.012–0.018 inches), or thick 
 (0.018–0.030 inches) grafts, depending on the amount of
dermis included. 1 Full-thickness skin grafts are defined as grafts composed of the epidermis and the
entire dermis.
Many factors play into the choice between a split- and full-
 thickness skin graft for wound coverage.
Primary contraction of a skin graft is due to elastin fibers within the dermis and occurs immediately after
harvest. The amount of primary contraction that a graft experiences is proportional to the amount of
dermis in the graft; therefore full-thickness grafts exhibit more primary contraction than split-thickness
grafts harvested from the same site. 5 By comparison, secondary contraction is a myofibroblast-mediated
process that occurs during graft healing and is more likely to occur in grafts with a thinner dermal
component. Secondary contraction can cause significant limitations in the stretch and mobility of the
healed graft, and therefore, full-thickness grafts are favored in areas such as wounds over joint surfaces
where mobility affects function. Although both split-thickness and full-thickness grafts are vulnerable to
shear forces during the healing process, once healed, grafts with a larger dermal element are less fragile
to subsequent trauma.
One must also take into account the size of the graft needed, as the harvest of a split-thickness graft heals
the donor site by secondary intention with minimal morbidity, whereas the donor site for a full-thickness
graft usually necessitates primary closure for optimal mitigation of donor site morbidity (thereby limiting
the size and potential donor sites for a full-thickness skin graft). Split-thickness grafts are also more
amenable to size expansion via meshing techniques, making them more suitable for large wounds.
Thicker skin grafts place greater metabolic demands on the wound bed during healing because of the
larger tissue component needing nutrients and eventual revascularization, with full-thickness grafts
having a slightly lower chance of complete survival and healing than split-thickness grafts on an
equivalent wound bed. Because they include only the most superficial portions of the dermis, split-
thickness skin grafts also generally do not contain intact accessory skin structures such as hair follicles
and sweat glands.
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Mechanisms of Skin Graft Healing
A healthy ungrafted wound bed will typically undergo healing by secondary intention—granulation,
contraction, and reepithelialization. Placing a skin graft on a wound bed fundamentally alters these
processes. Skin grafts become incorporated into the wound bed by a process known as graft take, a loosely
defined term generally accepted to imply graft healing and survival. This process is largely dependent on
the reestablishment of vascular perfusion to the graft within a critical time frame.
Skin graft take has historically been broken down into three classic phases of engraftment—imbibition (0–
48 hours), inosculation (48–72 hours), and revascularization (>96 hours). Much of our knowledge in this
area relies on decades-old research based largely on in vitro models and histologic analysis, and there
remain several competing theories of the exact mechanisms of graft revascularization. However, the
recent development of in vivo models has proven enlightening in repetitive intravital microscopic
analyses of the microcirculation and revascularization of a skin graft within the wound beds of live
organisms. 6
With all other factors being equal, graft survival has been shown to be dependent on the vascularity of
the donor site (with grafts harvested from a highly vascular area healing better than a graft from a poorly
perfused area), as well as the metabolic activity of the graft at the time of placement. Freshly harvested
grafts have also been shown to attract blood vessel ingrowth more rapidly than grafts that have been
frozen and subsequently thawed, but they are also less tolerant of the ischemic period because of
increased metabolic activity. 7
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Imbibition
The first stage of skin graft healing is an ischemic phase known as plasmatic or serum imbibition, a
concept first developed by Huebscher in 1888, 8 who theorized that grafts were initially nourished by
fluid from the wound bed prior to restoration of perfusion. The exact duration of this phase is variable
and depends on the characteristics of the wound bed. It lasts approximately 24 hours in a proliferative
wound and 48 hours in a fresh wound and can last up to several days in a poorly perfused wound bed.
Although it is widely accepted that imbibition allows the graft to survive the initial ischemic period until
perfusion is restored, the exact effects on the skin graft of this stage are unclear. Some believe that the
graft is nourished by the serum absorbed from the wound bed, 9,10 whereas others believe that the serum
has no metabolic function and only serves to keep the graft moist and its vessels patent in the initial
period following grafting. 8,11,12
During imbibition, plasma leaks from recipient capillaries into the wound bed-graft interface, and
fibrinogen in the plasma is converted into fibrin, which serves to adhere the graft to the wound bed. As
the grafts absorb serum, they become edematous and gain as much as 40% of their initial weight in the
first 24 hours, starting to decrease in weight after 96 hours, as lymphatic and venous return develop. 8
During imbibition, metabolism within the graft becomes anaerobic and the pH level falls, reaching a pH
of 6.8 as determined by Rous. 13 The metabolic demands of the graft also fall, with ATP levels falling 70%
and glucose levels falling 80%.
Historically, the second stage of skin graft healing was thought to be a process called inosculation, by
which blood vessels from the underlying wound bed connect with existing vessels in the skin graft at the
graft interface. This mechanism in its traditional definition is no longer considered truly valid, as it would
require close approximation of the cut ends of the wound bed and graft vessels. While connections
between the wound bed vessels and graft vasculature do occur, they are through the process of
angiogenesis and new vessel ingrowth in a unidirectional fashion from the wound bed into the graft.
Additionally, these new vascular connections do not necessarily occur at the wound interface with the
graft, as inosculation would infer. Recent animal studies have shown that after 48 to 72 hours,
microvascular growth of capillary-sized vessels (averaging 10–11 µm in diameter) from the wound bed
into the graft has been established in the fibrin interface of the wound. A peak in vessel density is seen at
postgraft day 7, with the vascular density at the interface increasing 2.5-fold between postgraft days 3 and
7 before returning to levels near those of postgraft day 3 by day 10. 14
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Revascularization
Historically, there have been three theories laid out to explain graft revascularization. The first proposes
that anastomoses are formed between the capillaries of the wound bed and the native vessels in the skin
graft, and that circulation is restored in the original skin graft vessels. 12,15–17 The second theory involves
new vessels originating from the wound bed growing into the skin graft and establishing a new
circulation after the initial reperfusion, implying angiogenesis and vasculogenesis, with the native graft
vessels eventually degenerating. 18–20 The third theory also suggests reperfusion by angiogenesis from the
wound bed but hypothesizes that recipient-derived endothelial cells migrating into the graft use the skin
graft’s intrinsic preexisting vascular network as a conduit for ingrowth, with eventual replacement of the
graft’s endothelial structure. 21 Recent development of in vivo animal models supports the third theory of
skin graft healing.
In 2010, an in vivo mouse model was developed by Lindenblatt et al. to model skin graft
revascularization, allowing for analysis of the microcirculation of the graft and wound bed using
fluorescein and intravital fluorescence microscopy during healing. 6 Microcirculatory analysis included
the determination of vessel diameter, red blood cell velocity, and functional capillary density defined as
length of perfused capillaries per area of observation. During the first 72 hours after grafting, there were a
progressive widening of the wound bed capillaries (from 10.6 ± 0.1 µm to 15.9 ± 0.2 µm) and the
development of small capillary protrusions representing early bud formation and angiogenesis, although
the skin graft still lacked reperfusion of the dermal plexus. At 72 hours, a sluggish blood flow within the
graft appeared in a pattern comparable to the original skin microcirculation at the donor site prior to graft
harvest, likely representing reperfusion of preexisting graft capillaries. After 96 hours, both the wound
bed and the skin graft demonstrated increased capillary diameter and functional capillary density,
indicating continued angiogenesis in the wound bed, and ingrowth of newly formed vessels into the graft
tissue. At 120 hours, capillary diameter and functional capillary density within the wound bed began to
decrease, while still increasing within the graft. By 10 days after grafting (240 hours), the skin graft was
fully revascularized, with the wound bed vessels still showing a slightly increased diameter (but without
signs of ongoing angiogenesis), and the capillary diameter and functional capillary density of the graft at
baseline.
This model supports the theory that angiogenesis is the primary factor in skin graft revascularization,
beginning as early as 24 hours after grafting, leading to vessel growth through the fibrin wound bed-graft
interface, eventually leading to reperfusion of the graft’s native microcirculation within 48 to 72 hours,
predominantly within the center of the skin graft. These findings are supported by previously
demonstrated dermal graft vessel growth of 5 µm/h, which would mean that a skin graft 200 to 300 µm in
thickness would be fully traversed by new microvessels within 48 to 72 hours. 21 Additional research by
Lindenblatt et al. has demonstrated that the graft vessels demonstrate an angiogenic response to
reperfusion between 3 and 8 days post grafting, suggesting that they are more than simply mechanical
conduits. Buds visualized within the grafts at capillary junctions contained endothelial cells and pericytes
on histology, indicating a temporary angiogenic response within the skin graft. 22
Matrix metalloproteinases MT1-MMP and MMP-2 are associated with the initiation of angiogenesis, by
promoting the degradation of the endothelium and interstitial matrix. MT1-MMP enables endothelial
cells to form invading tubular structures and to lyse the existing capillaries, as these invading structures
connect the graft and wound bed vasculature. The temporary angiogenic buds of the graft showed
increased expression of MT1-MMP on their surface and served in vivo as docking points for ingrowing
capillaries. MMP-2 expression was concentrated around the vessel sprouts of ingrowing vessels as they
advanced toward the deep dermal layer of the skin graft. 23
Using a crossover wild-type/green fluorescent protein (WT/GFP) skin transplantation mouse model
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(where WT skin was grafted onto GFP mice), GFP-positive structures appeared within the graft vessels
starting 48 to 72 hours after transplantation. Preexisting vascular channels in the periphery of the skin
graft were 100% replaced by vessel ingrowth from the wound bed by day 10, whereas those in the center
of the graft were replaced to a much lesser extent (50%–60%). 24 This may be because the hypoxic stimulus
for angiogenesis is no longer present after subsequent revascularization and nutrient supply in the center
of the graft where the revascularization process started. 25
In conclusion, skin graft healing is a process of imbibition and revascularization, which represents a
combination of angiogenic vessel outgrowth originating in the wound bed, reperfusion of the preexisting
graft vasculature, and partial replacement of the existing graft vessels.
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Histology of the Healing Skin Graft
During the first 4 days after grafting, the epidermis of the graft doubles in thickness. This has been
hypothesized to be due to multiple processes, including swelling of the nuclei and cytoplasm of
epidermal cells, epidermal cell migration to the surface of the graft, and accelerated mitosis of follicular
and glandular cells. 26 Between the fourth and eighth days after grafting, the epithelium continues to
proliferate and starts to desquamate. This increased cellular turnover does not return to baseline until
4 weeks after grafting. 27,28
The dermis of a healing skin graft also demonstrates considerable turnover of its cellular and noncellular
structures. It is generally accepted that fibroblasts within the dermis of a healing skin graft are not native
graft fibroblasts. In a rat model, Converse and Ballantyne noted decreased fibrocyte populations in the
first 3 days after grafting, with the appearance of new fibroblast-like cells after day 3, which would also
coincide with graft reperfusion. 18 Collagen turnover in the dermis parallels that of the epidermal
hyperplasia, peaking at 2 to 3 weeks after grafting at three to four times faster than the collagen turnover
rate for normal skin. Approximately, 85% of the original collagen in a skin graft is replaced within
5 months of grafting, although split-thickness grafts replace only half as much of their original collagen
compared with full-thickness grafts of the same size. 29,30 Elastin within the graft is also replaced, with
degeneration from postgraft day 3, and regeneration starting 4 to 6 weeks after grafting.
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Graft Contraction
Graft contraction occurs in both split-thickness and full-thickness grafts. Primary contraction occurs
immediately after graft harvest and is a result of the recoil of elastin fibers in the dermis. A full-thickness
graft loses approximately 40% of its surface area after harvest because of primary contraction, whereas a
split-thickness graft loses 10% to 20% of its area. Secondary contraction occurs during the healing of a
skin graft and is a myofibroblast-mediated process that is inversely proportional to the amount of dermis
in the graft. 31
The mechanism behind the inhibition of wound contraction by the presence of dermal elements in the
graft is unclear, although multiple hypotheses have been proposed. Rudolph had suggested that
increased dermis causes more rapid turnover and elimination of the myofibroblasts that mediate wound
contraction. 32 However, further studies by Oliver et al. demonstrated that grafts without dermal cells and
other noncollagenous dermal proteins, but possessing a collagen matrix, in fact behave much like full-
thickness skin grafts in terms of inhibiting wound contraction. 33 Once wound contraction is complete,
full-thickness grafts are able to grow with the surrounding tissue, whereas split-thickness grafts remain
fixed. 5
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Skin Grafting Techniques
Choosing a Donor Site
A skin graft donor site is selected based on several factors. Split-thickness grafts are commonly taken
from the lateral thigh to minimize difficulties during harvest and dressing changes, although patients
may prefer donor sites with less visible scarring such as the buttocks. Split-thickness grafts taken from the
scalp are also successful with minimal donor morbidity and no visible scarring once hair has regrown,
but are less commonly used because of the need to shave the donor area prior to taking the graft.
Common full-thickness graft donor sites include the inguinal creases, the postauricular region, and the
supraclavicular area. Consideration must also be taken to obtain an appropriate color match, especially
with head and neck skin graft reconstruction, with grafts optimally taken from donor sites above the
clavicles.
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Graft Fixation
Adherence of the skin graft to the wound bed during the revascularization process is critical for graft
survival. During imbibition, the graft adheres to the wound bed by a thin fibrin layer. Once
revascularization begins, vascular ingrowth from the wound bed into the graft reinforces this bond. Shear
forces, fluid collections (hematoma/seroma), and infection all decrease the chances of graft adherence and
take. For these reasons, optimal graft fixation methods minimize movement, and gently compress the
graft to reinforce hemostasis and minimize the chance of fluid collections. Tie-over bolsters using a
xeroform sheet filled with mineral oil–soaked cotton balls are common, especially for the fixation of
smaller grafts.
For larger skin grafts, grafts in mobile areas, or grafts in areas that are difficult to bolster (e.g., the hand
and axilla), negative-pressure dressing techniques such as vacuum-assisted closure therapy (KCI, San
Antonio, TX) have become increasingly popular as an alternative bolster dressing for meshed skin grafts.
Negative-pressure therapy allows the patient to maintain mobility; however, it does require the patient to
carry and recharge the negative-pressure device unit, and the attachment of the dressing to the unit may
prove to be cumbersome, especially in patients at increased risks for falls. Spray fibrin sealants such as
Evicel (Ethicon, Somerville, NJ) and Artiss (Baxter Healthcare, Deerfield, IL) are also gaining popularity
for both securing the edges of the graft (instead of sutures or staples) and increasing adherence of the
graft surface. They offer the benefit of immediate mobility, minimal dressings, and ease of application.
However, these products may be cost prohibitive in certain settings and also work optimally on thin split-
thickness grafts without much primary contraction.
The initial dressing over a skin graft is usually removed approximately 1 week following grafting, once
adherence of the graft to the wound bed is more secure and the revascularization process has begun.
However, adherence does not imply full graft survival and healing, and local wound care (typically with
xeroform and gauze to keep the wound moist and minimize shear forces) is necessary in the postacute
phase following the removal of the initial dressing until the skin graft has had the opportunity to mature
and become more durable, usually by 3 to 4 weeks following grafting.
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Causes of Graft Failure
In addition to mechanical factors in the fibrin interface between the wound bed and graft that interfere
with revascularization (such as hematoma, seroma, or shear forces), other causes of graft failure include
infection, medical comorbidities of the patient (such as diabetes mellitus, peripheral arterial disease, or a
history of radiation), and inherent properties of both the wound bed and the graft. Meshing (performed
using a hand-driven roller instrument that creates uniform slits throughout the graft) and pie-crusting
(using a scalpel to create multiple small fenestrations in the graft) are common techniques intended to
avoid fluid buildup under the skin graft.
Skin grafts in diabetic patients with associated comorbidities often demonstrate delayed healing, with one
study showing skin grafts take approximately 2 weeks longer to heal in diabetic patients than in
nondiabetic patients. 34 Diabetic patients are also at increased risk for wound dehiscence, infection, and
the need for revision surgery. Lower extremity peripheral vascular disease (PVD) also plays an important
role in the ability of the wound bed to support a healing graft needing revascularization. In patients
whose clinical pictures suggest PVD, a low threshold should be maintained for obtaining noninvasive
vascular studies and arteriography. These patients may be candidates for surgical bypass or endovascular
angioplasty techniques to optimize blood flow to the wound bed.
A wound bed with necrotic tissue that is poorly perfused, is grossly infected, or has chronically exposed
bone or tendon (without periosteum or paratenon) is not appropriate for a graft and will need to be
optimized prior to graft placement to maximize the chance of graft survival. Robson and Krizek found
that skin grafts are likely to fail if bacterial loads on quantitative culture are greater than 105 organisms
per gram of tissue. 35 Additionally, inherent properties of the graft may also play a role in graft failure. A
thin split-thickness graft will have a greater chance of engraftment than a full-thickness graft taken from
the same area, because the metabolic demands of the graft are less and a thinner graft requires a shorter
distance of new vessel ingrowth for full revascularization.
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Management of the Skin Graft Donor Site
The optimal dressing for the split-thickness skin graft donor site continues to be a matter for debate, as
multiple options exist and there are no comprehensive studies comparing all materials in a standardized
manner. Generally speaking, the ideal donor site dressing encourages rapid reepithelialization,
minimizes pain, decreases the risk of infection, and curtails scarring. In general, dressings that promote a
moist wound environment until reepithelialization occurs (at least 7 days) have been shown to improve
rates of healing and pain control.
A 2013 multicenter randomized clinical trial compared six common donor site dressings and assessed
both primary outcomes (time to reepithelialization and pain scores) and secondary outcomes (itching,
scarring, and adverse events such as infection, allergic reaction, and hypergranulation). 36 Patients were
randomly allocated to an alginate (Kaltostat; ConvaTec, Skillman, NJ; Algisite; Smith & Nephew, London,
UK; or Melgisorb; Mölnlycke Health Care, Gothenburg, Sweden); a semipermeable film (Tegaderm; 3M,
St Paul, Minnesota; or Opsite; Smith and Nephew); a gauze dressing (Adaptic; Acelity, San Antonio, TX;
or Jelonet; Smith & Nephew); a hydrocolloid (DuoDERM; ConvaTec); a hydrofibre (Aquacel; ConvaTec),
or a silicone dressing (Mepitel; Mölnlycke Health Care). Time to complete reepithelialization was 7 days
(30%) shorter when hydrocolloid dressings were used (median 16 days) than with any other dressing
(median 23 days). Pain scores were lowest in the semipermeable film group, but the difference did not
reach statistical significance. Gauze dressings had the highest infection rates.
This trial’s protocol prescribed the uniform use of gauze-based secondary dressings; therefore, the effects
of other secondary dressings (such as semipermeable film) used in clinical practice could not be studied.
Additionally, in clinical practice, other factors such as cost, patient compliance with wound care, and
availability must be considered. Skin graft donor site dressings continue to be a matter of surgeon
preference with no strong evidence directed to any one option. However, it is generally accepted that the
dressing should maintain a moist wound environment for at least 1 week.
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Emerging Alternatives to Conventional Skin Grafts
Cultured epidermal grafts have been used clinically since the 1980s, when burn patients were successfully
grafted with cultured allografts, 37 and Phillips et al. treated refractory chronic lower extremity wounds
with both cultured autografts and cultured allografts. 8 Although it seems intuitive that cultured
epithelial autografts would heal on a wound, the successful engraftment of cultured epithelial allografts
in the setting of complete lack of immunosuppression needed further explanation. In the 1990s, several
studies demonstrated that all donor cells in the graft were replaced by recipient keratinocytes by as early
as 1 week following grafting, 38–40 leading to the subsequent conclusion that cultured epidermal allografts
provide growth factors that lead to rapid wound healing despite the technical failure when the graft fails
to survive. This concept of an epithelial graft as a pharmacologic agent to aid wound healing rather than a
technical replacement of the epithelium was an important development in understanding how skin
substitutes and similar products may be used to promote wound closure.
The clinical applications of cultured epidermal autografts (Epicel; Genzyme, Cambridge, MA) have been
limited because of variable graft take rate, limited mechanical resistance, hyperkeratosis, scar contracture,
ulceration, and blister formation because of reactions to foreign fibroblasts in feeder media, as well as the
lengthy culture time (3–4 weeks) required and the high cost. Recently, there has been development of
several modifications of skin grafting technique to address the drawbacks of traditional skin grafting,
including dermal-epidermal grafts, fractional skin harvesting, and epidermal grafts. 41,42
In epidermal grafting, harvesting systems provide continuous negative pressure to separate the
epidermis from the dermis at the dermal-epidermal junction while preserving the histological
architecture of the epidermis. Although it has been used to treat vitiligo for decades, it has only recently
been evaluated as a possible treatment for wound healing. Healing of epidermal grafts is associated with
keratinocyte activation, growth factor secretion, and reepithelialization from the wound edge, more akin
to cultured keratinocytes than full- or split-thickness grafts. 42
Dermal-epidermal grafting creates micrografts of approximately 0.8 mm × 0.8 mm in size from a split-
thickness skin graft using the Xpansion Micrografting system (ACell, Colombia, MD). This increases the
border area and regenerative capacity of the grafts, and allows expansion by a factor of 1:100 (instead of
the typical 1:5 expansion of a full-thickness skin graft and 1:9 expansion of a meshed split-thickness skin
graft). Micrografts also do not need to retain their dermal orientation, thereby decreasing the procedural
complexity. This minimizes the size of the skin graft required and resultant donor site morbidity,
allowing the procedure to take place under local anesthetic in an outpatient setting. 41
Fractional skin harvesting requires harvesting a large number of full-thickness microscopic skin tissue
columns measuring approximately 700 µm in diameter using customized hypodermic needles. The
extracted skin columns are placed randomly in the wound without maintaining the dermal orientation.
Advantages of this technique include minimal morbidity, faster healing of the donor site without
scarring, and lack of the expanded mesh graft pattern of the healed graft. Although this is still a new
technique currently only being used in experimental animal models, it shows promise for future
commercial development. 41
Autologous noncultured cell therapy such as ReCell (Avita Medical, Royston, UK) isolates cells from the
dermal-epidermal junction of a thin split-thickness skin graft using trypsin incubation, followed by
mechanical agitation to separate the cells, and immediate suspension in a lactate solution, which then
undergoes spray application on the wound. Benefits of this system include quick application and a large
expansion ratio (1:80). Drawbacks include poor attachment and loss of cells secondary to mechanical
pressure while spraying, as well as high cost. One promising application of this technique is potential
one-stage creation of an epidermal layer when used concurrently with dermal matrices. In a pilot study, 43
ReCell was combined with the dermal substitute Integra (Integra LifeSciences Corp., Plainsboro, NJ) to
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treat full-thickness wounds in a porcine model. Cells isolated with the ReCell system were sprayed on the
underside of the dermal matrix prior to application. The study indicated that cells stay viable, migrate
through the dermal substitute, and self-organize into a differentiated epidermis.
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Skin Substitutes
The scarcity of donor site availability in patients with extensive burns and the suboptimal aesthetic and
functional outcomes commonly associated with autologous skin grafts have prompted the search for
viable substitutes for skin grafts. The earliest skin substitutes were allografts of cadaveric human skin
used to treat patients with extensive burns and limited donor sites for autograft harvest. The high
antigenicity of skin allografts, in particular the epidermal layer, with subsequent graft sloughing and
rejection led to the combination of cultured epidermal autografts over dermal allografts in the 1980s. 44
Observation that the formation of a neodermis comprised of healthy connective tissue is stimulated in the
wound bed even though the allograft does not successfully survive, as well as concerns about disease
transmission from donors and persistent scarring and contractures, has spurred continued efforts to
develop bioengineered skin substitutes. 45
In 1984, Pruitt and Levine 46 detailed the attributes of an ideal skin substitute:
Little or no antigenicity
Tissue compatibility
Lack of toxicity, either local or systemic
Permeability to water vapor just like normal skin
Impenetrability to microorganisms
Rapid and persistent adherence to a wound surface
Porosity for ingrowth of fibrovascular tissue from the wound bed
Malleability to conform to an irregular wound surface
Elasticity for motion of underlying tissues
Structural stability to resist linear and shear stresses
A smooth surface to discourage bacterial proliferation
Sufficient tensile strength to resist fragmentation
Biodegradability
Low cost
Ease of storage
Indefinite shelf life
Although the intervening decades have seen the development of a broad range of products that attempt
to embody many of these attributes, the term skin substitute belies how these products are currently used
in complex wound management. Furthermore, inconsistency in terminology and how these products are
applied can make consistent classification challenging, but skin substitutes and related products may be
categorized in several ways: composition of source material (e.g., synthetic versus biologic; human versus
animal), intended duration (permanent versus temporary), intended tissue to be replaced (epidermal
versus dermal), and number of layers (single versus bilaminate). Many products do not neatly fit into
these categories, however. For example, Biobrane (Smith & Nephew) is a biosynthetic composite
containing both synthetic elements comprised of silicone and a nylon mesh along with a biologic element
derived from porcine collagen. Another composite product, Dermagraft (Organogenesis, Canton, MA) is
created by seeding neonatal foreskin fibroblasts onto a biodegradable polyglycolic acid mesh. The
fibroblasts are cryopreserved at −80°C and regain their viability once the product is applied on the
wound, which must be done within 30 minutes after thawing. 45
Marketed under a variety of terms including artificial skin equivalent, dermal regeneration template,
wound matrix, biologic dressing, tissue scaffold, or some other permutation of these words, these
bioengineered products share the similar purpose of promoting wound closure, and contrasts are only
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found on whether the emphasis of a product is placed on acting as an in situ replacement of skin tissue
that is eventually incorporated into the recipient wound bed, or on promoting endogenous tissue repair
processes within the wound bed to achieve a more optimal healing outcome. In fact, rather than
evaluating these products as true substitutes for native skin and treating them as equivalent to
autologous skin grafts, it is more useful when deciding whether to use them for clinical purposes to
regard the role of these bioengineered skin products as constructs that may deliver growth factors and
extracellular matrix components, or attract cells to the wound bed, that can stimulate endogenous healing
processes to help promote wound closure and assist in preparing the wound bed for definitive surgical
treatment, especially for patients with wounds such as diabetic foot ulcers that can be extremely
challenging to treat. 45
One product mentioned more frequently on plastic surgery examinations is Integra, a bilaminar
membrane system consisting of a porous coprecipitate of bovine tendon type I collagen and shark
glycosaminoglycan (chondroitin-6-sulfate), covered by a temporary silicone epidermal substitute. The
silicone layer prevents excessive moisture loss and formation of granulation tissue on the matrix surface.
Chondroitin-6-sulfate provides elasticity to the matrix, controls the biodegradation rate, and maintains an
open pore structure that allows cell migration into the matrix. 49 Integra heals in phases similar to skin
graft healing, progressing through (1) imbibition, (2) fibroblast migration, (3) neovascularization, and (4)
remodeling and maturation. During imbibition, the interstices of the matrix fill with wound fluid
containing red blood cells, and the fibrin in the wound exudate fosters adherence of the matrix to the
wound bed. By day 7, myofibroblasts start migrating into the matrix and start producing collagen by the
beginning of week 3. The silicone epidermal layer has usually sloughed or been removed by this point in
time. New blood vessels can be seen in the deep portion of the matrix by 
 day 12 and reach the
superficial surface by day 28, at which point a thin split-thickness skin graft may be applied.
Recent data showed clinical effectiveness using Integra to help achieve eventual wound closure with
successful skin grafting performed as early as 1 week after Integra application in combination with
negative-pressure therapy. 50 However, neovascularization of the matrix at that early time point has yet to
be demonstrated at the histological level. Integra can also be used without the silicone layer as a filler for
contour deformities, although this does require a lengthier period of neovascularization for vessel
ingrowth through a thicker matrix. Though not uniform, empiric observations that use of this product,
especially in combination with other modalities such as negative-pressure wound therapy, can often
generate granulation tissue even over challenging surfaces, such as bone, tendon, and hardware, have led
to its off-label application for clinical situations where other methods of reconstruction are not feasible as
illustrated in the accompanying case (Figure 6.2).
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