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

Face
In the face, infiltrative anesthesia is most often employed because of the generalized application of
epinephrine and benefit of diffuse vasoconstriction in such a vascular tissue bed; however, minor
peripheral nerve blockade may provide targeted and sufficient analgesia when diffuse vasospasm is
unnecessary or undesirable or in addition to infiltrative anesthesia. 23
In the setting of cosmetic filler injection, facial nerve blockade functions well in the sensitive skin of the
midface and mouth. Perforation of the oral mucosa with a small-bore needle is generally less painful than
the highly innervated skin of the face. The infraorbital and mental nerves may be easily approached via
mucosal puncture to achieve analgesia of the entire lower and midface (Figure 12.1).
FIGURE 12.1 The infraorbital nerve is generally found at the intersection of a vertical mid-pupillary line and a horizontal line
drawn from the lateral margin of the ala. The mental nerve may be reliably infiltrated along the anterior mandible just inferior
and anterior to the first mandibular premolar. Each of these locations may be sufficiently anesthetized with 3 to 5 cc of local
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anesthetic. The supratrochlear nerve is commonly blocked at the same time and is found along the supraorbital rim 1 to 2 cm
medial to the supraorbital nerve. Both nerves may be blocked with the same injection in a supraperiosteal plane (2–5 cc).
Although less commonly used, blockade of the supraorbital and supratrochlear nerves may be utilized
for procedures on the forehead and scalp. The supraorbital nerve may be infiltrated on the supraorbital
rim in the mid-pupillary line.
Auricular blockade is an important adjunct in the repair of ear trauma both in the ER and OR. This is
especially true in the mangled ear where small flaps of potentially threatened skin must have their
viability serially assessed during repair for which infiltrative anesthesia would prove unacceptable.
Blockade of the ear may be accomplished by serial infiltration of the greater auricular and lesser occipital
nerves in the neck along the posterior border of the sternocleidomastoid muscle. Blockade of the
auriculotemporal nerve may be accomplished just anterior to the tragus. However, the ear cannot be
completely blocked in this manner, as terminal branches of cranial nerve ten and Arnold nerve will
require infiltrative anesthesia in the otic canal and conchal bowl if intervention is required in the central
ear (Figure 12.2).
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FIGURE 12.2 The ear, its sensory nerves, and cutaneous dermatomes.
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Hand
In the hand, minor nerve blockade is the cornerstone of procedural anesthesia. Here tourniquets may be
applied for procedural hemostasis and directed local anesthetic may be utilized to completely anesthetize
a single digit or the entire hand. Depending on the level of injury, anesthetics can be applied at multiple
levels of the hand, wrist, and arm to facilitate ER- or office-based hand procedures or to facilitate hand
surgery in the OR without the need of endotracheal intubation. In the OR, tourniquets are easily applied
to facilitate hemostasis in this very vascular tissue bed; however, when undesired, or when in the ER or
performing office-based procedures, the addition of epinephrine to infiltrated anesthetic in the hand and
digits has been proven safe and efficacious. 11,12
Complete digital anesthesia may be induced by infiltration of each individual digital nerve at the level of
the proximal phalanx on the volar-lateral surface of the digit (Figure 12.3A). Alternatively, the digits may
be blocked at the level of the metacarpophalangeal joint at their bifurcation. When a longer needle is
passed across the metacarpal heads, multiple fingers may be blocked with a single cutaneous puncture.
FIGURE 12.3 The course and relative location of the nerves of the hand. A. Expected locations and course of common and
proper digital nerves at the level of the metacarpophalangeal joint. B. Location of palmaris longus tendon in the wrist. C.
Anatomic location of the flexor carpi ulnaris tendon in the wrist. D. Area of superficial infiltration that would reliably block the
superficial branch of the radial nerve.
The median nerve is approached on the ulnar side of the palmaris longus at the proximal wrist crease
(Figure 12.3B). This approach avoids direct puncture of the median nerve, which typically lies
immediately below or radial to the palmaris longus tendon. Should the patient complain of lancinating
pain in the median nerve distribution, concern for direct nerve puncture should be raised and the needle
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removed and reinserted in a more ulnar location. The needle is advanced in line with the axis of the arm,
where 5 to 10 cc of long- or short-acting anesthetic may be infiltrated into the carpal tunnel.
The ulnar neurovascular bundle is located immediately deep to the flexor carpi ulnaris tendon and
proximal to the hook of the hamate (Figure 12.3C). Both structures are readily palpated on examination.
The needle is advanced horizontally, in an ulnar to radial direction under the flexor carpi ulnaris tendon.
Care must be taken to aspirate before infiltration to avoid intravascular injection in the ulnar artery.
When in the appropriate location 1 to 3 cc of local anesthetic may be infiltrated.
The superficial radial nerve emerges from the deep fascia of the arm along the lateral aspect of the radius
6 to 9 cm proximal to the radial styloid (Figure 12.3D). After this, it runs in the subcutaneous plane and
may be anesthetized by diffusely infiltrating the dorsoradial aspect of the wrist from the ulnar styloid
dorsally to the mid-dorsal wrist (3–10 cc).
The entire hand may be blocked at the level of the wrist by infiltration of the median, ulnar, and
superficial radial nerves with three cutaneous punctures.
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Regional Nerve Blocks
Regional nerve blockade can provide significant anesthesia to an entire region of the body such as the
entire arm or leg. Some of the most common examples include brachial plexus block, femoral nerve block,
TAP block, and spinal and/or epidural blockade. These procedures are most commonly performed by
anesthesia providers with the assistance of ultrasound guidance. These similarly may be used to provide
procedural anesthesia without the requirement of sedation but are generally associated with procedures
performed in the OR.
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Transversus Abdominis Plane Block
Transversus abdominis plane (TAP) block is a powerful adjunct for abdominal wall procedures ranging
from hernia repair to abdominoplasty and deep inferior epigastric artery perforator flap (DIEP) flap
harvest. Deep vein thrombosis (DVT) risk is theoretically augmented in abdominal wall procedures by
pain, which may inhibit postoperative mobility, and also augment pressure in the inferior vena cava,
which may lead to venous stasis in the legs and pelvis. 24,25
TAP block is commonly performed either preoperatively or intraoperatively for the management of post-
op abdominal pain. The abdominal wall is innervated by the branches of the intercostal nerves, which run
in the lateral abdominal wall on the superficial surface of the transversus abdominis muscle before
perforating the posterior rectus sheath at its lateral margin. These nerves may be blocked with ultrasound
guidance by infiltration of local anesthetic in the plane between the internal oblique muscle and the
transversus muscle. This important adjunct has been shown to improve postoperative pain control and
augment early mobilization protocols in reconstructive procedures involving the abdomen. 26,27
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Pectoral Nerve Block
Blockade of the medial and lateral pectoral nerves is a powerful pain control adjunct for breast surgery
and has been shown to decrease length of stay and narcotic utilization in the postoperative period. 28 The
pectoral muscle may be anesthetized via the medial and lateral pectoral nerves. These may be
approached in the plane between pectoralis major and minor just medial to the acromion. For cutaneous
anesthesia, the intercostal nerves may be accessed in the intercostal spaces of ribs 2 to 5. Blocking the
intercostal nerves lateral to the anterior axillary line will effectively anesthetize both the lateral and
medial intercostal perforating cutaneous nerves. These blocks may be performed under ultrasound
guidance by anesthesia providers or may be accomplished intraoperatively by the surgical team. 29
Pectoral block has been suggested by some authors as sufficient anesthesia for breast procedures without
the requirement of general anesthesia. 30
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Sedation
Sedatives that do not require endotracheal intubation are useful in plastic surgery. Plastic surgery
includes many procedures that may be carried out with local anesthesia alone or with the addition of a
sedative. 31 This is especially true in the care of pediatric patients in the ER setting where a sedative such
as midazolam (Versed) or ketamine may alleviate a great deal of unnecessary psychological distress for
smaller procedures that do not mandate progress to the OR. Sedation is also successfully used as a
preoperative adjunct to alleviate procedural anxiety.
The most common drugs utilized for sedation are midazolam, diazepam, fentanyl, and ketamine.
Propofol may also be used in the nonoperative setting in lower doses, but it is less commonly used
without the assistance of an anesthesia provider. The most common benzodiazepines, midazolam and
diazepam, differ chiefly in the duration of action. Midazolam is much shorter acting, lasting
approximately 3 hours. Diazepam is longer acting, 6 to 12 hours. These drugs are often utilized to
diminish patient anxiety during minor office-based procedures as an adjunct to local anesthesia. For more
involved procedures, they are sometimes combined with IV fentanyl for an additional analgesia effect.
The combination of infiltrative local anesthesia with the addition of a benzodiazepine and possibly also a
narcotic such as fentanyl are successfully used for myriad procedures both in and out of the OR. These
procedures range from the closure of simple lacerations to scar revision, smaller liposuction cases, a wide
variety of hand procedures, and even facelifts. 31
Ketamine is a powerful neuroleptic drug that at lower doses is used as an analgesic and at higher doses
induces a dissociative type of anesthesia. It is safe when administered in the appropriate setting.
Ketamine is a unique anesthetic because it does not depress the respiratory drive. Instead, the CNS
stimulant properties of ketamine may induce agitation and/or hypertension as side effects. Ketamine is
relatively contraindicated in hypertensive patients, though it is a good anesthetic in the hypotensive
patient. The chief advantage of ketamine anesthesia is that patients may be anesthetized without the need
for endotracheal intubation. 32
Onset of the drug when administered IV is immediate, and duration of up to 25 minutes may be
expected. Ketamine induces a dissociative (trancelike) state but also has analgesic and amnestic
properties. Anesthetic onset is often marked by the initiation of horizontal nystagmus. Hallucinations and
attendant verbalizations are also common which may be distressing to parents when the drug is
administered in the pediatric setting for ER-based procedures. If the parents of a pediatric patient are to
be present, it is recommended that these effects of the drug be explained in advance.
It is advisable that the surgical provider employ the assistance of a dedicated health care provider to
continuously monitor the airway and vital signs when anesthetic doses of ketamine are utilized. A patient
who has received anesthetic doses of ketamine is not able to protect their own airway. Nausea is a known
side effect of the ketamine, and these factors may culminate in a devastating aspiration event. An
appropriate period of NPO must be observed, and antiemetics may be administered prior to ketamine
dosing for prophylaxis.
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Questions
1. 30 minutes after digital injection with a solution of lidocaine and epinephrine for removal of a
small foreign body from the distal pad of the index finger that was otherwise untraumatized. The
digit remains cool, pale in color, and without capillary refill. What is the appropriate course of action
at this time?
a. Infiltration of phentolamine
b. Administer aspirin
c. Elevation of the extremity
d. Operative exploration for possible vascular injury
2. TAP block is a powerful anesthetic technique for abdominal procedures, wherein local anesthetic
is administered in the plane between these two muscles in the abdominal 
 wall.
a. Internal and external obliques
b. Internal oblique and transversus abdominis
c. Transversus abdominis and peritoneum
d. Rectus abdominis and posterior sheath
3. You are operating at a local outpatient surgery center, and one of the other surgeons is preparing
to perform a liposuction case. She states that she has just administered a dilute local anesthetic
formulation to the entire subcutaneous surface of the abdomen and flanks with a total lidocaine dose
of 30 mg/kg. What do you do next?
a. Inform the surgical team that a dangerously high dose of lidocaine has been administered.
b. Suggest that liposuction begin as soon as possible to quickly aspirate the local anesthetic
overdose.
c. Say nothing, as this is an acceptable dosage of subcutaneous lidocaine in this setting.
4. A patient informs you that they have an allergy to local anesthetics that causes diffuse hives and
sometimes even wheezing and shortness of breath. Which of the following are they most likely
having the allergic reaction to?
a. A preservative in the local anesthetic preparation
b. An amide moiety
c. An ester moiety
5. A patient undergoing facelift is administered a preoperative local anesthetic formulation of 0.25%
bupivacaine, 1% lidocaine and epinephrine. Shortly after subcutaneous infiltration, but before
incision, the patient goes into cardiac arrest. Anesthesia begins supportive measures with 100% FiO2
administered endotracheally, diazepam is administered, and chest compressions are commenced. It
is hypothesized that the cardiac arrest is due to the local anesthetic administered, and the
anesthesiologist is concerned about the duration of bupivacaine prolonging the resuscitative effort.
Lipid rescue is begun with a 20% IV lipid emulsion. What is the appropriate dose of this medication
in this setting?
a. 150 mL/kg
b. 500 mL/kg
c. 1.5 mL/kg
d
5 mL/kg
1. Answer: c. 30 minutes following infiltration of lidocaine and epinephrine into the digit, the digit
should not yet be expected to have robust capillary refill. Elevation of the extremity will most often
suffice for resolution of drug effect in digital epinephrine injection, as it aids in removal of the drug
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from the tissues of the digit. Phentolamine, although an option, would not yet be indicated in this
clinical scenario. Aspirin would not assist with this clinical scenario, as there is not a concern for
thrombosis of the digital arteries. Operative exploration would also not be indicated as in an
otherwise untraumatized digit, and in the presence of a known vasoconstrictor, the cause is both
known and temporary.
2. Answer: b. TAP block is administered by blockade of the intercostal nerves, as they run in the
lateral abdominal wall before they pierce the rectus sheath. At this level, they are found between the
transversus abdominis muscle and the internal oblique. This block is most often administered under
ultrasound guidance, by the anesthesia team.
3. Answer: c. It is not necessary to say anything in this setting. It is now well documented that doses
of 30 mg/kg administered in tumescent formulation is a safe and acceptable clinical practice. This
dose of lidocaine, administered in this manner, would be highly typical in today’s clinical practice.
4. Answer: a. True allergic reactions to local anesthetics are exceedingly rare. When allergic reactions
to infiltrated local anesthetics are seen in clinical practice, it is most often an allergy to para-
aminobenzoic acid, which is used as a preservative in the solutions. In the very rare case that a
patient does suffer a true allergy to local anesthetic, it is more often an allergy to ester local
anesthetics than amides.
5. Answer: c. Accepted dosage for lipid rescue in the treatment of local anesthetic toxicity consists of
an initial 1.5 mL/kg bolus of lipid infusion. This is then followed by continuous infusion. The exact
mechanism of lipid rescue is unknown; however, it is hypothesized that the intravascular lipid
functions as a lipid sink. In this way, lipid infusion draws the lipid-avid local anesthetic to the
intravascular space and away from the intracellular space of the vascular and cardiac tissues.
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References
Ueno, T, Tsuchiya, H, Mizogami, M, Takakura, K. Local anesthetic failure associated with inflammation: verification of the acidosis
mechanism and the hypothetic participation of inflammatory peroxynitrite. J Inflamm Res. 2008;1:41-48.
Swerdlow, M, Jones, R. The duration of action of bupivacaine, prilocaine and lignocaine. Br J Anaesth. 1970;42(4):335-339.
Miller, RD, Miller, RD, Eriksson, LI. Miller’s Anesthesia. 7th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.
Kvisselgaard, AD, Mosbech, HF, Fransson, S, Garvey, LH. Risk of immediate-type allergy to local anesthetics is overestimated-results from 5
years of provocation testing in a Danish allergy clinic. J Allergy Clin Immunol Pract. 2018;6(4):1217-1223.
Hallen, B, Uppfeldt, A. Does lidocaine-prilocaine cream permit painfree insertion of IV catheters in children? Anesthesiology. 1982;57(4):340-
342.
Bunke, J SR, Hult, J, Malmsjo, M. Buffered local anesthetics reduce injection pain and provide anesthesia for up to 5 hours. J Plast Reconstr
Aesthet Surg. 2018;71(8):1216-1230.
Best, CA, Best, AA, Best, TJ, Hamilton, DA. Buffered lidocaine and bupivacaine mixture - the ideal local anesthetic solution? Plast Surg
(Oakv). 2015;23(2):87-90.
Cepeda, MS, Tzortzopoulou, A, Thackrey, M, Hudcova, J, Arora Gandhi, P, Schumann, R. Adjusting the pH of lidocaine for reducing pain on
injection. Cochrane Database Syst Rev. 2010;(12):CD006581.
De Jong, RH, Heavner, JE. Diazepam prevents local anesthetic seizures. Anesthesiology. 1971;34(6):523-531.
Marwick, PC, Levin, AI, Coetzee, AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced cardiac arrest. Anesth Analg.
2009;108(4):1344-1346.Important analysis of the long duration of bupivicane induced cardiovascular depression, which can recur even after successful
resuscitative effort.
Lalonde, D, Bell, M, Benoit, P, et al. A multicenter prospective study of 3,110 consecutive cases of elective epinephrine use in the fingers and
hand: the Dalhousie Project clinical phase. J Hand Surg Am. 2005;30(5):1061-1067.The largest and most rigorous study to date documenting the
excellent safety profile of epinephrine in digital anesthesia.
Chowdhry, S, Seidenstricker, L, Cooney, DS, et al. Do not use epinephrine in digital blocks: myth or truth? Part II. A retrospective review of
1111 cases. Plast Reconstr Surg. 2010;126(6):2031-2034.
Klein, JA. Tumescent technique for local anesthesia improves safety in large-volume liposuction. Plast Reconstr Surg. 1993;92(6):1085-
1098.Posits that does up to 35 mg/kg lidocaine, much higher than manufacturer recommended doses are likely safe when administered in highly dilute
tumescent solution formulations in liposuction cases.
Rubin, JP, Bierman, C, Rosow, CE, et al. The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of
lidocaine. Plast Reconstr Surg. 1999;103(3):990-996.
Swanson, E. Prospective study of lidocaine, bupivacaine, and epinephrine levels and blood loss in patients undergoing liposuction and
abdominoplasty. Plast Reconstr Surg. 2012;130(3):702-722.Case series evaluating blood levels and toxicity associated with local anesthetic
infiltration in liposuction cases finding that, though the technique is safe, only 20% of infiltrated local anesthetic is removed with the lipoaspirate.
Lynch, C III. Depression of myocardial contractility in vitro by bupivacaine, etidocaine, and lidocaine. Anesth Analg. 1986;65(6):551-559.
Ciechanowicz, S, Patil, V. Lipid emulsion for local anesthetic systemic toxicity. Anesthesiol Res Pract. 2012;2012:131784.
Kelton, PL. Local anesthetics, cocaine, and CPR. Select Read Plast Surg. 1992;7(5).
Fleming, JA, Byck, R, Barash, PG. Pharmacology and therapeutic applications of cocaine. Anesthesiology. 1990;73(3):518-531.
Golf, M, Daniels, SE, Onel, E. A phase 3, randomized, placebo-controlled trial of DepoFoam(R) bupivacaine (extended-release bupivacaine
local analgesic) in bunionectomy. Adv Ther. 2011;28(9):776-788.
Gorfine, SR, Onel, E, Patou, G, Krivokapic, ZV. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in
patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum.
2011;54(12):1552-1559.Along with reference 19, the basis for FDA approval of Exparel. Though the drug elutes over 48 hours, improvement in pain
control was not seen beyond 24 hours.
Rabin, T. FDA in Brief: FDA Approves New Use of Exparel for Nerve Block Pain Relief Following Shoulder Surgeries. 2018.
Diepenbrock, RM, May, JR, Cone, WR, Ehland, EL. Patient preference for preprocedural anesthetic prior to facial cosmetic injectable fillers.
Am J Cosmet Surg. 2017;34(3):143-149.
Willenberg, T, Clemens, R, Haegeli, LM, et al. The influence of abdominal pressure on lower extremity venous pressure and hemodynamics:
a human in-vivo model simulating the effect of abdominal obesity. Eur J Vasc Endovasc Surg. 2011;41(6):849-855.
Pannucci, CJ, Alderman, AK, Brown, SL, et al. The effect of abdominal wall plication on intra-abdominal pressure and lower extremity
venous flow: a case report. J Plast Reconstr Aesthet Surg. 2012;65(3):392-394.
Sforza, M, Andjelkov, K, Zaccheddu, R, et al. Transversus abdominis plane block anesthesia in abdominoplasties. Plast Reconstr Surg.
2011;128(2):529-535.
Araco, A, Pooney, J, Araco, F, Gravante, G. Transversus abdominis plane block reduces the analgesic requirements after abdominoplasty
with flank liposuction. Ann Plast Surg. 2010;65(4):385-388.
Shah, A, Rowlands, M, Krishnan, N, et al. Thoracic intercostal nerve blocks reduce opioid consumption and length of stay in patients
undergoing implant-based breast reconstruction. Plast Reconstr Surg. 2015;136(5):584e-591e.
Lanier, ST, Lewis, KC, Kendall, MC, et al. Intraoperative nerve blocks fail to improve quality of recovery after tissue expander breast
reconstruction: a prospective, double-blinded, randomized, placebo-controlled clinical trial. Plast Reconstr Surg. 2018;141(3):590-597.
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Moon, EJ, Kim, SB, Chung, JY, et al. Pectoral nerve block (pecs block) with sedation for breast conserving surgery without general anesthesia.
Ann Surg Treat Res. 2017;93(3):166-169.
Iverson, RE. Sedation and analgesia in ambulatory settings. American Society of Plastic and Reconstructive Surgeons Task Force on Sedation
and Analgesia in Ambulatory Settings. Plast Reconstr Surg. 1999;104(5):1559-1564.
Ersek, RA. Dissociative anesthesia for safety’s sake: ketamine and diazepam : 
 a 35-year personal experience. Plast Reconstr Surg.
2004;113(7):1955-1959.
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C H A P T E R 1 3
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Concepts of Tissue Engineering
Matthew D. Treiser and William G. Austen
Key Points
Tissue engineering is defined as the application of the principles and methods of engineering and life
sciences toward the fundamental understanding of structure-function relationships in normal and
pathological mammalian tissues and the development of biological substitutes for the repair or
regeneration of tissue or organ function.
Regenerative medicine seeks to use the natural regenerative properties of cells to repair the body,
whether by direct tissue formation or by the release of trophic factors to induce endogenous healing.
Tissue engineering and regenerative medicine currently employ three main strategies:
Implantation of isolated or cultured cells for injection and subsequent healing
In situ directed tissue regeneration
Implantation of ex vivo assembled constructs containing cells and scaffolds
The main cell sources utilized in tissue engineering are cultured somatic cells lines, embryonic stem
cells, adult stem cells, and induced pluripotent stem cells.
Tissue engineering may provide solutions to commonly encountered clinical challenges in plastic
surgery; however, to date, few devices and/or products have gained wide clinical use.
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Tissue Engineering and Regenerative Medicine
Tissue loss, chronic disease and end organ failure present an enormous social and economic strain on the
afflicted individuals and society at large. In the United States, the treatment of these patients costs over
$400 billion per year with over eight million surgical procedures performed annually to treat these
disorders. 1 Although tissue loss, chronic disease, and end organ failure encompass a heterogeneous
grouping of pathologic conditions ranging from liver failure to musculoskeletal injury, current surgical
interventions often fail to provide curative solutions. Traditional treatment strategies depend on
extracorporeal devices, such as kidney dialysis machines, or operative interventions, such as the
allografting of organs from living/cadaveric donors and free tissue transfer. Although these approaches
have provided positive patient outcomes for some, many patients fail to receive viable long-term cures.
Unfortunately, current transplantation approaches suffer from extreme shortages in donor organs and
not all patients with organ failure are candidates. In 2017, 125,737 patients were registered for organ
transplants, while only 34,771 organs were transplanted. 2 These data underestimate the true need, as
studies have demonstrated that there are about 730,000 deaths in the United States annually from end
organ disease. 3 Non–transplantation-based surgical reconstructions also frequently fail owing to their
associated postoperative complications and further suffer from donor site morbidity. For these reasons
and others, current surgical and mechanical interventions often fail to provide adequate curative
solutions to tissue loss and organ failure. The ideal solutions would recreate whole organ function in
corporeal devices that are biocompatible and easily integrated into the patient’s anatomy.
Tissue engineering and regenerative medicine seek to facilitate the healing of tissues and organs lost to
pathological processes via the development of devices/biologics that stimulate, supplement, or act in lieu
of the body’s natural regenerative abilities. The term tissue engineering was defined at an National science
foundation meeting in 1988 as, the “application of the principles and methods of engineering and life
sciences toward the fundamental understanding of structure-function relationships in normal and
pathological mammalian tissues and the development of biological substitutes for the repair or
regeneration of tissue or organ function.” 4 Although the terms tissue engineering and regenerative medicine
are often used synonymously, it is important to note that although they share the same end purpose, the
terms imply subtly different approaches. Tissue engineering focuses on the creation and formation of
biological substitutes, whereas regenerative medicine seeks to utilize the natural regenerative properties
of cells to repair the body, whether by direct tissue formation or by the release of trophic factors to induce
endogenous healing. 5 To clarify, regenerative medicine functions by stimulating cells to repair damaged
tissue, whereas tissue engineering utilizes engineered constructs to reform solid tissues or organs. These
strategies are not mutually exclusive and often a given approach for tissue repair represents a
combination of both tissue engineering and regenerative medicine. Proponents of these strategies believe
they can address the clinical needs of patients suffering from organ or tissue loss by developing
biologically derived constructs that maintain the functionality of the original organ or tissue. These
constructs would reduce the need for whole organ donation and surgical repair by providing artificial
surrogates that are nonimmunogenic and effectively perform the functions of endogenous tissues.
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Strategies in Tissue Engineering and Regenerative Medicine
Historically, attempts by physicians to artificially induce tissue regeneration date back to 1500 bc. 6 These
early attempts at nasal reconstruction utilized autologous grafted skin in conjunction with wood scaffolds
to reform the nose. In its modern formulation, tissue engineering and regenerative medicine currently
employ three main strategies 7 (Figure 13.1):
Implantation of isolated or cultured cells for injection and subsequent healing
In situ directed tissue regeneration
Implantation of ex vivo assembled constructs containing cells and scaffolds
FIGURE 13.1 The three main strategies in tissue engineering: (1) implantation of isolated or cultured cells for injection and
subsequent healing; (2) in situ directed tissue regeneration; and (3) implantation of ex vivo assembled constructs containing
cells and scaffolds.
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Injectable Cell Therapies
The interest in injectable cell therapies, particularly injectable stem cell therapies, derives from their
avoidance of a surgical procedure and associated complications, the enormous availability of cell sources
in the form of aspirates from donors, and the replacement of only damaged cells rather than whole
organs. 5 Studies have shown some success in both animal models and clinical applications with this
strategy for repair of cardiac function in heart disease. 8 However, the true feasibility and effectiveness of
this approach remains unclear. Although injection of stem cells appears to improve cardiac function, a
clinical review published by Collins et al. indicates that few of the injected cells are retained in the heart
and that most improvements in cardiac function are more likely a result of stimulated angiogenesis via
secreted cytokines rather than via reparation of cardiac tissue. 9 This review highlights some of the
greatest criticisms of the injectable approach. First, although some cells may localize to the wound site,
the lifetime of those cells and the location and consequences of the remainder of the injected cells within
the body remain concerns. Second, the benefit of injecting stem cells may be artifact, with the greatest
benefit derived from secreted soluble factors as opposed to tissue reformation. 8 Finally, even though this
approach may be adequate for the repair of focally damaged tissue, it is not expected to provide
restoration of whole organ failure because it is believed that isolated cells cannot themselves form new
tissues in the absence of a supporting material.
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In Situ Tissue Regeneration
In situ tissue regeneration depends on the ability of the native cells within the body to synergize with an
acellular implanted device. This device may be permanent or degradable, and the material may be
natural (e.g., fibrin, gelatin, thrombin, collagen, cadaveric decellularized matrices) or synthetic. In
contrast to prostheses for which the ultimate goal is to provide an artificial replacement, here the device
acts as a scaffold for endogenous cell repair. The scaffold provides the mechanical support necessary to
maintain functional form. The material may include bioactive or biomimetic factors to promote cellular
attachment, proliferation and/or differentiation thereby promoting tissue regeneration. In situ tissue
engineering devices have shown clinical promise in applications such as sutures, orthopedic devices,
tissue sealants, and hernia repair devices. Interestingly, most of the work performed involving in situ
tissue regeneration focuses on the repair of focal defects in connective tissues (i.e., bone, cartilage,
tendons, and skin). Investigators focus on focal defects because, in situ, avascular scaffolds only allow
cells to penetrate 100 µm owing to oxygen diffusion limitations. 10 Although some work has been
attempted to simultaneously promote cell migration and angiogenesis within a scaffold, to date, the
creation of microvasculature networks in situ remains suboptimal. 11 Therefore, in the absence of a
previously established vascular network or an angiogenic material, tissue engineering strategies that
utilize acellular constructs focus on applications in which oxygen diffusion is nonlimiting.
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Cell-Material Hybrids
The final tissue engineering strategy uses cells seeded within a porous implant to create a cell-material
hybrid (Figure 13.2). In these constructs, cells are isolated from donors (autologous or allogeneic) and
seeded onto biomaterial scaffolds in vitro. The cells are cultured on the scaffolds within a bioreactor until
they assemble an organized tissue similar to that of the damaged tissue the device is intended to repair.
Once implanted, this artificially engineered organ functions as native tissue. This approach interests
researchers because it addresses many of the weaknesses of the other two. Unlike both the injectable and
in situ regeneration paradigms, the cell-material hybrid strategy, in theory, allows for the construction of
a whole living organ ex vivo.
FIGURE 13.2 Osteoblasts seeded on a porous, three-dimensional poly (polymer carbonate) scaffold. Cells are imaged at
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72 hours and stained with calcein AM for living cells (green) and ethidium homodimer-1 for dead cells (red). The scaffold (blue)
was imaged in reflection mode. The image is a maximum projection image from 50 individual slices taken every 10 microns
(100×).
Assembling the tissue ex vivo allows researchers to construct complex structures that mimic the natural
biology of endogenous tissue. For example, utilizing micro patterning and machining, vascular networks
can be assembled and combined with the cell-material hybrid to provide adequate perfusion of the
construct. Additionally, as opposed to in situ differentiation, the ex vivo approach assembles spatially
controlled tissue analogues of multiple cell types within scaffolds that are seeded uniformly with viable
cells. Finally, the cell-material hybrid approach provides the testing of the engineered tissue before
implantation to ensure that it functions properly. This technique has been clinically demonstrated in the
fabrication and implantation of a tissue-engineered bladder device as described by Atala et al. 12 They
reported on the isolation and ex vivo expansion of bladder cells on collagen/polyglycolic acid scaffolds
with clinical implantation in cystoplasty candidates. Although this approach shows much promise, it is
not without its current limitations. The cell-material hybrid approach suffers from the complexity of the
system and the difficulty in correctly tuning the multiple facets of the approach. Creating scaffolds that
promote cell differentiation while maintaining mechanical integrity is challenging, but in conjunction
with directing cell phenotypic behaviors, these constructs often do not produce desired outcomes. This
complexity is evident by the dearth of clinical products to date that have employed these techniques.
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Cell Sources for Tissue Engineering
Fully Differentiated Somatic Cell Lines
Fully differentiated somatic cells and stem cells represent the two most commonly used cell sources for
tissue engineering. Somatic cells demonstrate the potential for tissue regeneration when seeded in
artificial scaffolds. Examination of review articles within the literature shows that these cells have been
applied in organs such as the cartilage, 13 pancreas, 14 bone, 15 skin, 16 and liver. 17 Although these reviews
highlight the potential terminally differentiated cells provide, these cells suffer from difficulty in
balancing differentiation with proliferative ability. Cell proliferation provides the cell numbers that are
critical for tissue construction. Ideally, a small amount of donor cells expand to homogenously populate
the scaffold. Unfortunately, as explained by Strehl and coauthors, terminally differentiated somatic cells
often lose their ability of self-renewal. 18 Although methods exist to reinitiate cell proliferation in these
cells, this process may result in the downregulation of differentiation behaviors. Thus although these cells
are terminally differentiated and therefore should demonstrate the desired cell phenotypes, obtaining
adequate cell numbers to create constructs of adequate size and cell density often perturbs their desired
phenotypes. Furthermore, somatic cells are often difficult to culture ex vivo, limiting their utility.
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Stem Cells for Tissue Engineering
In an attempt to find a cell source that maintains both proliferative and differentiation potentials,
researchers have turned to stem cells. Stem cells are pluripotent cells (i.e., have the ability to differentiate
into a number of terminal cell types) that display self-renewal in their stem-like states (Figure 13.3). These
stem cells may be isolated from human embryonic tissues or from niches within adult tissues such as, but
not limited to, the bone marrow, liver, skin, adipose tissue, and brain. Other sources of these stem cells
use techniques to derive them from human somatic cells lines via genetic manipulation creating induced
pluripotent stem cells (iPSCs). 19,20 These techniques induce both pluripotency and self-renewal
capabilities in fully differentiated somatic cells. All of these stem cell types require either the
downregulation of immunogenic markers or the isolation of these cell sources from the ultimate recipient,
as the elicitation of an immune response results in destruction of the construct. Stem cells are of great
interest because their immunogenicity can be tailored so as to provide little to no response promoting
integration into the recipient. Stem cells provide the abilities of self-renewal, pluripotency, and immune
tolerance that make them ideal cell source candidates for tissue engineering and regenerative medicine
approaches.
FIGURE 13.3 Stem cells in the presence of external stimuli have the potential for differentiation to somatic cell types or self-
renewal and expansion with maintenance of their stem-like state.
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Adult Stem Cells
Adult stem cells represent a readily obtainable class of potential stem cells. Adult stem cells are
multipotent progenitor cells isolated from adult donors. They can be derived from a number of tissues;
however, the most extensively used in cell therapies are those derived from the bone marrow or adipose
tissues, also known as human mesenchymal stem cells (hMSCs). hMSCs have gained interest in the
scientific community because of their multipotency, specifically their ability to differentiate into a
multitude of mesenchymal cell phenotypes including, but not limited to, smooth muscle cells,
chondrocytes, osteoblasts, and adipocytes. Bone marrow or fat aspirates from donors provide a readily
available supply of these stem cells, with a number of isolation and propagation procedures to enrich this
population. 21 hMSCs are a self-renewing cell population allowing for their use in both injectable cell
approaches and strategies that utilize the ex vivo expansion and seeding of cells onto scaffold materials
intended for implantation. The successful creation of constructs that integrate scaffold materials and
hMSCs requires the expression of the appropriate differentiated cellular phenotypes post seeding. Unlike
other cell sources that will be discussed below, the differentiation potential of hMSCs are somewhat
limited in their abilities to become cell phenotypes that are not of the mesenchymal lineages (i.e.,
difficulty forming ectodermal and endodermal derived tissues).
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Embryonic Stem Cells
Human embryonic stem cells (hESCs) are a cell source extracted from human embryonic tissues that
maintain the abilities of self-renewal and differentiation to multiple cellular phenotypes. James Thomson
and his colleagues first identified these cells from the blastocysts of in vitro fertilization–donated human
embryos in 1998. 22 hESCs immediately garnered interest owing to their pluripotent capabilities that
promote differentiated phenotypes of all derivatives including ectodermal, endodermal, and
mesenchymal lines. Cell types that have been demonstrated in vitro to arise from hESCs include neurons,
skin, hematopoietic cells, hepatocytes, pancreatic cells, endothelial cells, cardiac and skeletal muscle cells,
chondrocytes, adipocytes, and osteoblasts. 23 These immortalized cell lines provide a foundation for the
understanding of the cellular mechanisms driving cellular proliferation and cell fates. The versatility of
the cells in terms of near limitless proliferation in conjunction with unrestricted differentiation thrust this
cell source to the forefront of early tissue engineering and regenerative medicine efforts. However, the
use of human embryos to derive these cell lines has generated ethical concerns that have limited public
funding and use of these lines.
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Induced Pluripotent Stem Cells
In an effort to create cells that have the same pluripotency and self-renewal capabilities without the
ethical concerns, iPSCs were created. Using research derived from hESC research, Yamanaka et al.
identified factors (Oct3/4, Sox2, c-Myc, and Klf-4) whose expression resulted in dedifferentiation of
somatic cells to the stem cell phenotype. 19,24 These iPSC-generated cell lines had self-renewal and
pluripotency similar to hESCs but without the ethical concerns. However, iPSC cells and hESCs are not
identical, as they share only approximately 4% of their gene expression profile. 19 The expression of these
Yamanaka factors is produced via viral transfection and subsequent expression by the somatic cells. This
raises concerns for possible mutagenesis and teratogenesis in clinical applications. The potential for
tumorogenesis is present for all stem cells, as the potential for unrestricted growth is the hallmark of both
stem cells and oncogenic cells.
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Stem Cell Differentiation
The paradigm for the use of stem cells (regardless of the type of stem cell used) in tissue engineering and
regenerative medicine involves the expansion of a cell population that can then be steered to differentiate
to the desired cell phenotype. Methods for steering this differentiation can involve the application of
soluble factors, the application of mechanical stimuli, or the binding of specific ligands. Although the
process of differentiation is different for individual cell types, as an example, the process of stem cell
differentiation toward bone is discussed to demonstrate the concepts involved (Figure 13.4). The process
of osteoblastic differentiation is believed to proceed largely via stimulation with soluble factors. In vitro,
osteogenic induction of stem cells is generally achieved via application of media containing
dexamethasone, ascorbate, and β-glycerophosphate. This combination of soluble factors can achieve high
levels of bone differentiation. 25 It is believed that osteoblastogenesis proceeds via transcription and
subsequent activation of the osteoblast-specific core-binding factor a1 (Cbfa1), also commonly referred to
in the literature as runt-related transcription factor 2 (RUNX2). Cbfa1 is the earliest and most specific
marker of osteoblastogenesis and induces cells to produce type I collagen and alkaline phosphatase, both
early markers of osteoblastic differentiation, signifying the preosteoblastic stage. Although soluble factors
play a dominant role in osteoblastogenesis, they are not the only signals involved. Cell adhesion
molecules such as integrins, selectins, cadherins, the arginylglycylaspartic acid polypeptide–binding
sequence found in collagen, fibronectin, osteopontin, thrombospondin, bone sialoproteins, and
vitronectin have all been shown to be required for differentiation. 26–28 Finally, material mechanics can
influence stem cell differentiation toward the osteoblastic phenotype, with the greatest osteoblastogenesis
occurring when stem cells are cultured on stiffer materials. 29,30 Thus, the production of differentiated cell
phenotypes from a stem cell represents a complicated and robust process requiring a number of chemical
and mechanical cues. Tissue engineering and regenerative medicine strategies all utilize some
combination of soluble factors, mechanical cues and/or scaffolds to direct cell (somatic and stem) fates in
predictable manners as described in the example above. It is this interplay that remains essential to the
understanding and creation of viable constructs.
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FIGURE 13.4 Human mesenchymal stem cells, in vitro, differentiate to osteoblasts via application of dexamethasone,
ascorbate and β-glycerophosphate (DAG). DAG activates a cascade resulting in the upregulation of the earliest osteoblastic
marker, Cbfa1. Osteoblastogenesis has also been shown to act via the Wnt pathway, in which Wnt3a, an active form of β-
catenin, forms a complex with LRP5, which also results in upregulation of Cbfa1. Upregulation of Cbfa1 induces the expression
of Dlx-5, which coincides with differentiation to the preosteoblastic stage signified by production of alkaline phosphatase and
type I collagen. Terminal differentiation to the osteoblastic phenotype is characterized by production of late osteoblastic markers
including mineral, osteocalcin, osteopontin, and other noncollagenous proteins.
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Scaffolds for Tissue Engineering
Many of the strategies in tissue engineering utilize biomaterials as tissue scaffolds. A degradable and
resorbable material is desired so that once the defect is repaired, only native/implanted tissue remains.
Optimally, the degradation and resorption rate of such a scaffold should be tuned so that the falloff in
scaffold strength is compensated with an increase in tissue growth. Naturally occurring matrices such as
collagen, hyaluronic acid, and decellularized complete extracellular matrices (ECMs) have all been seeded
with cells to create tissue engineering constructs. 31 Furthermore, polymeric scaffolds are promising
candidates for engineering new tissues because they offer a wide array of materials with three-
dimensionality, tunable surface chemistry and degradation rates, an assortment of physical parameters,
incorporation of bioactive substances (i.e., growth factors, cytokines, adhesive proteins), and various
scaffold architectures (Figure 13.5). 32
FIGURE 13.5 Alizarin red mineral staining of poly(polymer carbonate) scaffold. This scaffold is made to form a porous material
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that allows fluid and nutrient flow along with architecture conducive to cell seeding.
Polymeric biomaterials utilized for clinical needs today, like the poly(α-hydroxy ester)s, were not created
explicitly for tissue engineering but were adapted from preexisting materials. Unfortunately, the
implementation of biomaterials that were not designed a priori to meet biologic applications often results
in materials that have nonspecific or unidentified reactions with tissues, decreasing the efficacy of the
implant. The ability to tailor endogenous or synthetic materials to promote cellular functions such as
motility, proliferation, and stem cell differentiation provides the prospect of composing complex
multicellular tissues in vitro and represents one of the first steps in the realization of engineered whole
organ regeneration. To date, the ideal materials have not been identified, and there remains no consensus
on whether synthetic or natural occurring scaffolds hold more promise.
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Plastic Surgery and Tissue Engineering
Plastic surgery uses tissues and materials in conjunction for reconstructive purposes. If tissue engineering
focuses on the creation of biological substitutes for the repair or regeneration of tissue or organ function, then
plastic surgery, with its focus on tissue manipulation techniques (e.g., composite tissue
allotransplantation and free tissue transfer), may be described as the clinical practice of tissue engineering.
For these reasons, plastic surgeons have often been at the forefront of the development and adoption of
tissue engineering and regenerative medicine strategies. Some tissue engineering applications that are
pertinent to plastic surgeons are discussed below. This list is not meant to be exhaustive but to highlight
some of the areas in clinical medicine utilizing tissue engineering solutions with pertinence to plastic
surgeons.
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Skin Substitutes and Chronic Wounds
Chronic wounds represent a debilitating injury to patients, and the treatment of these conditions remains
difficult and costly. Local tissue rearrangement and serial debridement strategies are the mainstay of
treatment but often suffer from recurrence and eventual wound breakdown. Commercial products that
use tissue engineering and regenerative medicine approaches that are currently available for wound
healing generally fall into three categories: acellular products for structural matrices, cellular products,
and growth factor products. Currently there are approximately 27 commercially available acellular
products. 33 These products are constructed using a combination of synthetic and naturally occurring
materials (e.g., collagen in conjunction with silicone sheeting, decellularized matrices, fibrin) without
cells. These products promote wound healing by improving the wound microenvironment and/or
providing temporary coverage to protect the wound from contamination. Unfortunately, as these
products lack a cellular component, they are entirely dependent on the synergy with endogenous tissue
for healing. In situations when recipient-site tissue healing capacity may be impaired, these products do
not provide long-term solutions. Cellular products typically utilize cultured keratinocytes with synthetic
scaffolds. Some products include fibroblasts along with the keratinocytes and scaffolds. Currently, they
are nine commercially available cellular products for skin and chronic wound treatment. 33 Skin
substitutes, to date, stimulate wound healing by the production of matrix proteins and other soluble
factors that influence cell migration and angiogenesis. 33 These constructs lack sources of progenitor cells
and are, therefore, self-
 limited. 34 Thus, healing with these products is via augmentation of natural
healing rather than recapitulation. Growth factor products simply use soluble factors to promote healing
in a regenerative medicine capacity. There are two products on the market that seek to increase wound
healing via the delivery of platelet-derived factors. Although all of these devices hold promise, none has
been able to mimic the healing capacity of native skin. The difficulty in skin and wound healing tissue
engineering stems from the complex interplay between multiple cell types and even tissues that promote
skin homeostasis. The need for a device that fulfills the barrier functions of skin but maintains the ability
for cellular proliferation and renewal represents the greatest barrier to whole skin tissue engineering. 34
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Fat
Interest in adipocyte or fat tissue engineering stems from its relevance to disease models for obesity,
diabetes, and other lipodystrophic disorders, 35 as well as from recent cosmetic and reconstructive
advances to address volume depletion and soft tissue loss. Autologous fat grafting techniques have been
developed to isolate adipocytes and fat-derived stem cells. 36 However, these autologous tissue transfer
techniques suffer from graft loss and scarring. Plastic surgeons and tissue engineers alike have
investigated cells harvested in lipoaspirates as cell sources for tissue-engineered constructs. 37 Adipocytes
are harvested from the lipoaspirate and expanded on three-dimensional scaffolds that hope to maintain
form and volume. Early work has demonstrated retention of form for up to 4 weeks after implantation
through adipogenesis. 34,37 Further work has examined the ex vivo expansion of the fat-derived stem cells
with subsequent reimplantation. These studies have demonstrated potentially improved volume
retention with engineered fat as compared with traditional aspirates. 38 To date, tissue-engineered fat has
remained largely experimental; however, the abundance of adipocyte cell source has made fat tissue
engineering one of the most investigated tissue constructs.
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Cartilage
Cartilage consists of a largely avascular arrangement of chondrocytes within a dense ECM. This lack of
vascularity results in decreased healing and self-repair. Pathologic conditions of cartilage include
decreased joint function and tissue deformities. For these reasons and others, commercial tissue-
engineered cartilage products have been developed and tested clinically. These products hope to address
the lack of endogenous healing potential of cartilage and promote healing and repair. Commercial
products have been developed using implantation of isolated or cultured cells for injection and
subsequent healing and implantation of ex vivo assembled constructs containing cells and scaffolds.
Autologous chondrocytes have been harvested, expanded ex vivo, and reimplanted in cartilaginous
lesions. These approaches depend on the ability to create chondrocytes and increase cell numbers
utilizing soluble factors in both two-dimensional and three-dimensional cultures. Techniques have been
developed utilizing both scaffold- and non–scaffold-based constructs. The non–scaffold-based strategies
focus on cell expansion to deliver viable chondrocytes to the diseased tissue. Unfortunately, these
approaches often lack the mechanical stability needs of load-bearing cartilage. In terms of scaffold-based
approaches, hydrogels, decellularized xenogeneic matrices, freeze-dried scaffolds, woven and nonwoven
microfiber meshes, and 3D-printed scaffolds have all been investigated. 39 These scaffolds can be based on
naturally occurring ECM molecules (e.g., collagen and hyaluronic acid) or new synthetic molecules.
Clinical indications for these products include the treatment of pathologic conditions of articular surfaces
secondary to trauma and osteoarthritis for orthopedic purposes and in ear and tracheal reconstruction.
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Bone
Musculoskeletal injuries cost Americans over $215 billion yearly, with fractures representing more than
half of the injuries. The loss of bony tissue secondary to trauma, cancer, or primary bone disease results in
significant mortality, morbidity, and socioeconomic loss. Current surgical techniques to address large
volume bony loss focus on reparation via autologous tissue transfer with either bone grafting or free
tissue transfer or bone transport mechanisms. Tissue engineering approaches have been developed and
investigated to address these injuries without the donor site morbidity or lengthy process for bone
transport. Most of these devices use synthetic polymer and processed biologic materials to provide
acellular osteoconductive scaffolds with and without osteoinductive ligands. For example, previously
tested constructs used human decellularized bone allograft doped with bone morphogenetic protein 2 to
promote osteoinduction and osteoconduction. 40 However, more recent work has focused on the creation
of ex vivo assembled constructs seeded with endothelial cells and hMSCs. 41 The goal of these devices is
to provide a load-bearing construct that, when implanted, maintains a rich vascular network with a
preformed lattice of viable osteoblast and osteocytes. Although these devices show promise, they have
yet to obtain wide acceptance clinically. To date, an integrated tissue engineering solution providing
structural, vascularized bone constructs for large bone defects remains to be clinically translated.
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Conclusion
Regardless of the strategy or tissue, tissue engineering, in its current form, has not delivered as billed. In
1995, US-based market analysts predicted that tissue engineering would generate $3 billion by 2002. In
reality, the total tissue engineering market in 2002 was less than $50 million. 42–45 In 2016, the tissue
engineering still only reached $2.2 billion in sales. Although many factors contribute to the current
inability for tissue engineering to provide off-the-shelf tissues, perhaps the greatest is the lack of
fundamental understanding regarding cells, materials, and how they interact. Because the two main
components of tissue-engineered constructs are the cells and scaffolding material, these two factors and
their interactions must be understood and optimized to maximize the efficacy of the approach. 7 A 2007
study performed by Johnson et al. surveyed 24 leaders of the tissue engineering field to determine the
best paths to obtain clinically viable products. 46 Their findings indicated that one of the most needed
areas is the understanding and control of stem cell behavior by measuring responses at the molecular
level. Using these structure-function responses of stem cells probed at the molecular level may enable the
identification of biomarkers for guidance in the design of tissue-engineered products. To that end, a
strategic assessment of the field from the US Government Multi-Agency Tissue Engineering Science
group of federal agencies provided a list of the critical priorities to identify these structure-function
relationships, including 47
Understanding the cellular machinery
Identifying and validating biomarker and assays
Advancing imaging technologies
Defining cell/environment interactions
Establishing computational modeling systems
The US Government Multi-Agency Tissue Engineering Science assessment indicates that these five
priorities are essential to accomplishing what they consider the four overarching goals of the field 46,47 :
Understanding and controlling the cellular response
Formulating biomaterial scaffolds and the tissue-matrix environment
Developing enabling tools (i.e., high-throughput assays, instrumentation, imaging modalities, and
computational modeling)
Promoting scale-up, translation, and commercialization
Therefore, current efforts have focused on the fundamental science driving tissue engineering. It is hoped
that with new developments tissue engineering may become an essential and valued tool to the
reconstructive surgeon.
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Questions
1. Strategies used in tissue engineering and regenerative medicine include which of the following
(choose all that are correct)?
Implantation of isolated or cultured cells for injection and subsequent healing
Autologous tissue transfer
In situ directed tissue regeneration
Implantation of ex vivo assembled constructs containing cells and/or scaffolds
a. i
b. i and iv
c. ii
d. i, iii, and iv
e. All of the above
2. Cell sources that maintain the ability to differentiate to all germ cell lines utilized in tissue
engineering and regenerative medicine include which of the following?
Somatic cell lines
Adult stem cell lines
Embryonic stem cell lines
Induced pluripotent cell lines
a. i
b. ii and iii
c. iii
d. iii and iv
e. All of the above
3. Which of the following scaffold materials represents a 
 synthetic rather than a naturally occurring
cell matrix?
a. Collagen
b. Poly-α-hydroxy esters
c. Hyaluronic acid
d. Fibronectin
e. Decellularized human tissues
4. Stem cell differentiation to the osteoblastic phenotype is 
 influenced by which of the following
factors in vitro?
a. Soluble cues
b. ECM proteins and cell adhesion molecules
c. Mechanical properties of the scaffolds
d. None of the above
e. Answers a, b, and c
1. Answer: d. Tissue engineering and regenerative medicine currently employ three main strategies:
(1) implantation of isolated or cultured cells for injection and subsequent healing; (2) in situ directed
tissue regeneration; and (3) implantation of ex vivo assembled constructs containing cells and
scaffolds. Autologous tissue transfer is traditionally utilized by plastic surgeons to treat tissue loss
but is not used in tissue engineering strategies. The goal of tissue engineering is to create biologic
devices that act in lieu of traditional treatment modalities, such as autologous tissue transfer.
2. Answer: d. Somatic cell lines represent terminally differentiated cells that are unable to change cell
lines. They are traditionally limited to the cell phenotype from which they are derived. For example,
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somatic neurons do not possess the ability to differentiation to muscle and other nonneuronal cells.
Adult stem cells are cells that maintain the ability of self-renewal and have the ability to differentiate
to certain but not all germ cell lines. For example, bone marrow–derived stem cells typically can
differentiate to any mesenchymal stem cell lineages including bone, muscle and fat but not
ectodermal tissues such as neurons. Embryonic stem cell lines and iPSC lines have the ability to
become any of the germ cell lines. The induced pluripotent cells are reengineered with the Yamanaka
factors to allows the cells to become stem cell like.
3. Answer: b. Poly-α-hydroxy esters are synthetic polymers derived from the monomer of lactic acid.
It is synthesized through the ring-opening polymerization of the lactone. Common materials in the
family include poly(L-lactic acid) and poly(glycolic acid). These polymers are degradable but have
acid breakdown products (lactic acid) with their degradation. Collagen, hyaluronic acid, fibronectin,
and decellularized human tissues are all naturally occurring. They can be processed into multiple
forms including hydrogels, meshes, and porous scaffolds.
4. Answer: e. In vitro, osteogenic induction of stem cells is generally achieved via application of
media containing dexamethasone, ascorbate, and β-glycerophosphate. This combination of soluble
factors can achieve high levels of bone differentiation. Cell adhesion molecules such as integrins,
selectins, cadherins, the arginylglycylaspartic acid polypeptide–binding sequence found in collagen,
fibronectin, osteopontin, thrombospondin, bone sialoproteins, and vitronectin have all been shown to
be required for osteoblastic differentiation. Finally, material mechanics can influence stem cell
differentiation toward the osteoblastic phenotype, with the greatest osteoblastogenesis occurring
when stem cells are cultured on stiffer materials.
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Stosich, MS, Mao, JJ. Adipose tissue engineering from human adult stem cells: clinical implications in plastic and reconstructive surgery.
Plast Reconstr Surg. 2007;119(1):71-83; discussion 84-75.
Bashir, MM, Sohail, M, Bashir, A, et al. Outcome of conventional adipose tissue grafting for contour deformities of face and role of ex vivo
expanded adipose tissue-derived stem cells in treatment of such deformities. J Craniofac Surg. 2018; 29(5):1143-1147.
Huang, BJ, Hu, JC, Athanasiou, KA. Cell-based tissue engineering strategies used in the clinical repair of articular cartilage. Biomaterials.
2016;98:1-22.
Jones, AL, Bucholz, RW, Bosse, MJ, et al. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction
of diaphyseal tibial fractures with cortical defects: a randomized, controlled trial. J Bone Joint Surg Am. 2006;88A(7):1431-1441.
Ren, L, Kang, Y, Browne, C, et al. Fabrication, vascularization and osteogenic properties of a novel synthetic biomimetic induced membrane
for the treatment of large bone defects. Bone. 2014;64:173-182.
Kohn, J, Welsh, WJ, Knight, D. A new approach to the rationale discovery of polymeric biomaterials. Biomaterials. 2007;28(29):4171-4177.
Lysaght, MJ, Hazlehurst, AL. Tissue engineering: the end of the beginning. Tissue Eng. 2004;10(1-2):309-320.
Lysaght, MJ, Nguy, NA, Sullivan, K. An economic survey of the emerging tissue engineering industry. Tissue Eng. 1998;4(3):231-238.
Lysaght, MJ, Reyes, J. The growth of tissue engineering. Tissue Eng. 2001;7(5):485-493.
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C H A P T E R 1 4
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Standardization of Photography and Videography
in Plastic Surgery
Frank Yuan and Kevin C. Chung
Key Points
High-quality photography is critical in the presentation of surgical outcomes, assurance of standards,
and advancement of surgical education.
Maintaining a high level of consistency requires several factors to be tightly controlled—camera
equipment, lighting, patient positioning, background, patient clothing, and magnification/size.
Defining and promoting a standardized set of guidelines when shooting different areas of interest on
the body promotes effective analyses and comparison of outcomes.
An important goal of preoperative and postoperative videos is to capture the functional changes in
specific areas of interest that result from different operative techniques to facilitate evaluation of
outcomes.
High-quality intraoperative videos capture the dynamic aspects of surgery and add important
context to facilitate understanding of scientific presentations.
An effective video operator must know and understand the procedure being performed, as well as
all the pertinent steps and relevant anatomy; thus no time is wasted by the operating surgeon during
the critical steps of an operation.
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Importance of Medical Photography
High-quality photographic documentation is essential in plastic surgery. Not only are they useful for
scientific presentations and manuscripts, but more importantly, preoperative and postoperative
photographs are used as tools to evaluate and track surgical outcomes, and often serve as benchmarks for
quality standards. 1,2 Intraoperative photographs of procedures can also document operations and
outcomes for educational and medicolegal purposes, as well as providing context for communication
among residents and attending surgeons. 2 Lastly, these photographs are essential in shaping public
perception. 3 In the age of social media, patients are often inundated with online before and after images of
other patients, particularly on cosmetic practice websites. Consequently, plastic surgeons and their
practice groups are often judged before ever meeting the patient. 4,5
Thus, maintaining standardization and optimizing photographic quality establishes the perception of
quality for a surgeon. Even miniscule oversights in the photographing process by the plastic surgeon
(e.g., photographs that are blurry, or contain extraneous surgical instruments or anatomy with no
pertinence to the subject of the photograph) will detract attention from the theme they are trying to depict
and, consequently, diminish the photograph’s educational value (Figure 14.1). 2
FIGURE 14.1 A. Example of a bad surgical photo. The surgeon’s and assistant’s hands, excess blood, and misplaced gauze
and surgical instruments all distract from the focus of the picture. B. Example of a good surgical photo. The view is
unobstructed and allows the viewer to be drawn to the focal point of the picture.
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Maintaining Consistency
The key to great medical photography is consistency—taking every photograph the exact same way every
time. To maintain a high level of consistency, several factors have to be tightly controlled, e.g., camera
equipment, lighting, patient positioning, background, patient clothing, and magnification/size.
6
Fortunately, as technology continues to improve and modern-day cameras become more advanced,
several parameters, such as aperture, shutter speed, and the sensitivity of the image sensor to light (i.e.,
ISO), which were once manually adjusted, are now set according to an installed algorithm. Each of the
different automatic camera settings (e.g., sport, portrait, landscape) represents a different exposure
algorithm, optimized to achieve the best combination of these parameters. 6 Thus, the quality of
photographs with most of today’s cameras will be excellent. Nevertheless, several considerations in the
photographic process are operator dependent and should still be thoroughly considered to maintain a
high level of quality and consistency.
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Equipment
When ensuring high-quality photographic documentation in plastic surgery, two main camera types
should be considered—a digital single-lens reflex (SLR) 35 mm camera or a point and shoot digital
camera. 7,8 The digital SLR 35 mm camera offers the possibility of a variation of lenses. We recommend
having one lens with a short focal length range of 50 to 60 mm, which is ideal for body contouring and
photographs that use a large area, and a lens with a longer focal length range of 90 to 105 mm, which is
ideal for closer photographs of the face and head (Figure 14.2). These high-quality lenses assure a
maximum depth of field and minimal alteration of colors. Additionally, these lenses produce minimal
distortion, whereby creating a flat field and, ultimately, an accurate depiction of the body area
photographed without the bulging that occurs with wide-angle lenses. Whichever the lens selected, all
lenses should have macro capabilities, which helps the photographer focus on objects close to the camera
lens. 7,8
FIGURE 14.2 A shorter focal length produces a wider angle of view, whereas a longer focal length produces a narrower angle
of view.
Aside from SLR cameras, some surgeons recommend the use of point and shoot cameras, particularly for
intraoperative photographs. The point and shoot camera offers the advantages of not being too
cumbersome, is practical and easy to operate (even for first-time users), and is cheaper on average, while
still being able to provide high-quality images that satisfy the stringent requirements necessary for
medical photography. 2
Regardless of the camera type, we highly recommend using a camera that has the capability to project a
grid screen in its viewfinder, which can ensure that patients are properly aligned within the viewfinder
frame. Precise framing of anatomic landmarks both preoperatively and postoperatively will guarantee
consistency and reproducibility. 7-9 Additionally, it is beneficial for the camera to have a swivel screen so
the operator is able to shoot a wide array of angles, particularly for intraoperative photographs where it
may be difficult to position oneself over a sterile field. 2
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Background
The choice of background and maintenance is extremely important and has a significant impact on the
quality of medical photographs. It is essential that the background is even, nonreflecting, and
monochromatic. 2,7,9 Any degree of unevenness or clutter will detract from the focus of the image and
diminish its value. After multiple tests of different background colors, the Clinical Photography
Committee has decided that a sky blue background is the most visually pleasing, independent of whether
the photograph is taken in black-and-white or in color. Furthermore, a sky-blue background provides a
sufficient color contrast to various skin tones and diminishes the appearance of shadows. 7,10,11 Black,
white, and even green have all been used as background colors. However, a white background tends to
produce harsh shadows, whereas a black background tends to provide less contrast for darker-skinned
patients. 2,7,9
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Lighting
Lighting is one of the most crucial aspects of medical photography when it comes to maintaining
consistency. Thus, using different types of lighting for preoperative and postoperative photographs is
unacceptable. Classically, there are three main types of light sources that may be used—a ring light, a
mounted strobe light, and a studio light. 12 The ring light, located circumferentially around the lens, is the
simplest and most foolproof source of light. Although it is technically impossible to alter the angle of the
light source to the patient, the drawbacks to the ring light are its availability and flat lighting (i.e., little or
no contrast or gradients of light to define shapes). A camera-mounted strobe light has the advantage of
producing side lighting and negates the problem of flat lighting. However, maintaining consistent
preoperative and postoperative lighting with the mounted strobe light relies heavily on the
photographer’s ability to keep it positioned in a constant relationship to the patient at all times. Perhaps,
the most effective form of lighting is studio lighting. However, it requires that photographs are taken
with the same lighting at consistent angles every time. Otherwise, for instance, underexposed side
lighting will emphasize contour irregularities, whereas overexposed front lighting will de-emphasize
contour irregularities. 12 Maintaining specific lighting arrangements for each corresponding body area of
interest should be facilitated with labels throughout the studio to better direct the patient, as well as the
camera operator. 12,13 If equipment is not available, it is acceptable to use the built-in flash on a camera, as
long as it is in a well-lit room; poor lighting conditions create shadows and uneven lighting. 2
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Areas of Interest
To maintain accuracy and consistency between preoperative and postoperative photographs, patient and
camera positions must be kept constant. Thus, a standardized set of guidelines for each of the various
areas of the body should be utilized. 14 Not only are standardized guidelines important when comparing
one’s own preoperative and postoperative photographs, they are important when comparing
preoperative and postoperative photographs among different surgeons as well.
A comprehensive set of guidelines were established in 2006 by the American Society of Plastic Surgeons
(ASPS) and the Plastic Surgery Foundation (PSF). 14 Despite the significance of these published
guidelines, only approximately 66% of ASPS and ASAPS plastic surgeons adhered to these guidelines. It
is unclear if this discrepancy was attributed to surgeon preference, technique, or unclear patient
instructions. 5 And although it may not be possible for all plastic surgeons to exactly conform to a set of
guidelines owing to inexperience or availability of equipment or studio space, promoting and striving to
adhere to a standardized set of guidelines will facilitate surgeons to critically analyze and compare
outcomes, and review results and ensure quality standards.
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Guidelines for Photographs
Head (Figure 14.3)
FIGURE 14.3 A. Standard positioning and up close views of the face. Eyebrows positioned at the top of the frame; nose
centered horizontally in all views. B. Standard positioning and views of the mouth. The mouth centered vertically in all views
and horizontally in anterior views. C. Standard positioning and views of the full face. Ears centered vertically in all views. D.
Standard positioning and views of the ears. The head centered horizontally in anterior/posterior views; ears centered in close-
up views.
(Used with permission of the American Society of Plastic Surgeons.)
Patient should have their hair pulled away from the face and tucked behind the ears with a
headband or clip. All jewelry and eyewear, as well as heavy makeup and lipstick, should be
removed.
Patient should be seated on a stool and positioned at a premarked area in the examination room. The
patient should rotate the entire body (shoulder and feet) when turning for oblique and lateral views.
Facial expressions must be controlled so that they do not distort the surgical outcomes or the
deformities of interest.
Close-up face (Figure 14.3A): Eyebrows should be positioned at the top of the frame. The nose should
be centered horizontally in all views. For basal views, the tip of the nose should be aligned with the
upper eyelid crease.
Full face (Figure 14.3C): Ears should be centered vertically in all views. The head should be centered
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