P h y s i o l o g y o f Wo u n d
Healing
Eric A. Gantwerker, MS, MDa, David B. Hom, MDb,*
KEYWORDS
Scarring Scars Facial Wounds Healing
Skin histology
Self-Test Questions
The following questions are intended for the
reader to self-test. The answers, with full
background, are covered within this article.
This article originally published in Facial Plastic Surgery Clinics, August 2011, 19:3.
Disclosures: There are no affiliations, conflicts of interest, or financial disclosures by either author.
a
Department of Otolaryngology Head and Neck Surgery, University of Cincinnati and Cincinnati Childrens
Hospital Medical Center, 231 Albert Sabin Way, Cincinnati, OH, USA
b
Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology Head and Neck
Surgery, University of Cincinnati and Cincinnati Childrens Hospital Medical Center, 231 Albert Sabin Way,
PO Box 670528, Cincinnati, OH 45267-0528, USA
* Corresponding author.
E-mail address: david.hom@uc.edu
Clin Plastic Surg 39 (2012) 8597
doi:10.1016/j.cps.2011.09.005
0094-1298/12/$ see front matter 2012 Elsevier Inc. All rights reserved.
plasticsurgery.theclinics.com
Key Points
86
SKIN HISTOLOGY
Keratinocytes make up 95% of the epidermis, and
the stratum basale is the source of all replicating
keratinocytes. It is these keratinocytes in the basal
layer that are primarily responsible for the epidermal response in wound healing.4 As keratinocytes replicate they push older cells toward the
surface, and these cells progressively lose their
nucleus and take on a more flattened ovoid shape.
This stratified squamous keratinized epithelium
undergoes constant turnover, essentially regenerating fully every 48 days. The stratum basale sends
down finger-like projections that interdigitate with
similar structures reaching up from the dermis.
This process forms the rete ridges that are often
seen in cross section. Freshly healing wounds as
well as skin grafts lack these rete ridges initially,
Fig. 2. The many appendages of the epidermis and dermis. The pilosebaceous unit is the source of all stem cells
essential to the reepithelialization process. (Reprinted from Jenkins GW, Tortora GJ, Kemniitz CP. Anatomy and
physiology: from science to life. New York: J. Wiley and Sons; 2006. p. 14871. Chapter: 5; with permission.)
87
88
Hemostasis
Inflammation
Proliferation
Maturation/remodeling.
Although these phases are separated for simplicity reasons they in fact overlap a great deal, andeven different areas of wounds can be in different
phases of healing. Any interruption in the natural
cascade of healing can disrupt subsequent phases
Hemostasis
Hemostasis is the initial phase that occurs within
seconds to minutes after the initial insult. Initially
hemorrhage into the wound exposes platelets to
the thrombogenic subendothelium. Platelets are
integral to this phase and the entire healing
pathway, as they not only serve to provide initial
hemostasis but also release multiple cytokines,
hormones, and chemokines to set off the remaining
phases of healing. Vasoactive substances such as
catecholamines and serotonin act via specialized
receptors on the endothelium to cause vasoconstriction of the surrounding blood vessels. Smaller
vessels are signaled to vasodilate to allow the influx
of leukocytes, red blood cells, and plasma proteins. Platelets interact with the GpIIb-IIIa receptor
on the collagen of the damaged subendothelium to
become activated and form an initial clot. Activated
platelets release their granules and ignite the
extrinsic and intrinsic coagulation cascades. Fibrin
polymerization helps form a mature clot and serves
as scaffolding for the infiltrating cells (leukocytes,
keratinocytes, and fibroblasts) that are key to
subsequent phases of healing. Platelets release
Fig. 3. Time scale of the 4 phases of healing and the many processes that occur at each phase of healing. Any
disruption in these processes will ultimately delay healing and lead to scar formation. (From Enoch S, Price P.
Worldwide Wounds. Available at: http://www.worldwidewounds.com/2004/august/Enoch/Pathophysiology-OfHealing.html; with permission.)
Inflammation
The inflammatory phase is heralded by the influx of
neutrophils, macrophages, and lymphocytes to
the site of injury (Fig. 4). Neutrophils are the first
leukocytes on site, arriving en masse within the
first 24 hours. Neutrophils are soon followed by
macrophages, which are attracted by the byproducts of neutrophil apoptosis. Phagocytic cells
such as macrophages and other lymphocytes
appear in the wound to begin to clear debris and
bacteria from the wound. These macrophages
infiltrate at approximately 48 hours post injury
and stay until the conclusion of the inflammatory
phase. Macrophages have long been thought to
be the key cell to the wound-healing process,
and they seem to orchestrate the most important
phases of healing. Although they are integral to
proper healing, recent research has also looked
at their role in improper healing and scarring.
Studies of macrophage function have revealed
that these key cells are intricate in reepithelialization, granulation tissue formation, angiogenesis,
wound cytokine production, and wound contracture.7 Inflammation is a necessary step of the healing process, and inhibition of this key phase (via
anti-inflammatory medications) can result in improper healing. This phase of healing is important
to combat infection.8 If disrupted or prolonged
(ie, longer than 3 weeks), this inflammation can
lead to a chronic wound, impaired healing, and
eventually more scarring. Important factors that
can abnormally lengthen this phase of healing
include high bacterial load (greater than 105 microorganisms per gram of tissue), repeated trauma,
and persistent foreign material in the wound.6
Once the wound has been debrided, the repair or
proliferative phase begins.
Proliferation
The proliferative (repair) phase begins early on in the
form of reepithelialization (Fig. 5). The repair phase
also involves capillary budding and extracellular
matrix production to fill in the defects left behind
from debridement of the wound. Epithelialization
is marked by the proliferation and influx of keratinocytes near the leading edge of the wound. As discussed previously, stem cells within the bulbs of
the hair follicles and apocrine glands begin to differentiate into keratinocytes and repopulate the
stratum basale, and also begin to migrate over the
edge of the wound. Once they encounter the
mesenchyme of the extracellular matrix (ECM),
they attach near the inner wound edge and begin
to lay down a new basement membrane. Following
this, another row of keratinocytes migrates over the
newly laid epithelial cells to fill in the defect. These
cells migrate and digest the ECM using proteases
until they are in physical contact and they stop
migrating, signaled by contact inhibition from
neighboring keratinocytes.9 This reepithelialization
protects the wound from infection and desiccation.
89
90
Angiogenesis/Maturation
Angiogenesis follows a typical pattern of sprouting, looping, and pruning signaled by a complex
gradient of cytokines. These small and delicate
sprouting vessels repopulate the dermis, and any
trauma to this area will lead to destruction of these
vessels and delayed healing. Shearing of these
new vessels is often a problem in skin grafting,
whereby the graft is solely supplied by initial imbibition for 24 hours followed by growth of these
vessels into the tissue. It is the role of the bolster
placed over these delicate graft sites to prevent
hematoma that would limit diffusion of nutrients,
but more importantly to prevent shearing of these
delicate immature vessels. Bolsters are usually left
on for 5 to 7 days to allow these vessels to become
more robust and mature, and to resist these
shearing forces. Angiogenesis is also a key
process affected by primary versus secondary
closures. Angiogenesis is greatly accelerated by
primary closure, due to the proximity of the
budding vessels. In healing through secondary
intention, this process takes place through formation of the aforementioned granulation tissue
induced by hypoxia, elevated lactate, and various
growth factors. Healing by secondary intention
involves epithelialization over this granulation and
then extensive remodeling. Any medications that
interfere with new blood vessel formation (ie, the
antiangiogenic drug bevacizumab [Avastin]) can
be detrimental to wound healing.
Remodeling
The remodeling phase begins as the provisional
ECM and type III collagen is replaced with type I
collagen and the remaining cell types of the
previous phases undergo apoptosis (Fig. 6). With
the laying down of type I collagen, the tensile
Wound Strength
91
92
Fig. 8. The typical curve of the increase in wound tensile strength as time progresses. Strength plateaus around 4
to 5 weeks and reaches only 80% of its original strength. (Reprinted from emedicine: Wound healing, chronic
wounds. Available at: http://emedicine.medscape.com/article/1298452-overview; with permission.)
Box 1
A nonexhaustive list of the intrinsic and
extrinsic factors that affect healing
Intrinsic factors
Age
Fetus
Child
Adult
Medications
Steroids
Anticoagulants
Penicillamine
Cyclosporine
Reprinted from Hom DB, Odland R. Prognosis for
facial scarring. In: Harahap M, editor. Surgical techniques for cutaneous scar revision. New York: Marcel
Dekker; 2000. p. 2537; with permission.
Immune status
Hypertrophic scarring and keloids
Psychophysiological stress
Stress
Pain
Noise
Hereditary healing diseases
Ehlers-Danlos syndrome
Epidermolysis bullosa
Marfan syndrome
Osteogenesis imperfecta
Werner syndrome
Disease states
Chronic pulmonary disease
Chronic cardiac disease
Chronic liver disease (cirrhosis)
Uremia
Alcoholism
Diabetes
Peripheral vascular disease
Extrinsic factors
Malnutrition
Protein-calorie
Vitamins
Minerals
Infection
Insufficient oxygenation or perfusion
Hypoxemia
Hypoxia
Anemia
Hypovolemia
Smoking
Cancer
Radiation
Chemotherapy
93
94
95
96
Self-Test Responses
The following are correct responses to the self-test presented at the beginning of this article.
1. A 19-year-old woman is on isotretinoin (Accutane) for acne and has a facial acne scar that she wishes
to be dermabraded. What do you counsel the patient about?
Correct answer: She needs to be off the medication for 1 year to limit the risk of scarring
Incorrect:
She should continue the medication because the extra vitamin A will improve her healing.
You cannot resurface her acne scar because of the long-lasting effects of this medication.
Encourage 2 g of vitamin C daily for 2 weeks before the procedure.
2. A 73-year-old insulin-dependent diabetic man with a serum glucose level of 300 mmol/L comes to
your office for a rhytidectomy. How do you optimize your results?
Correct answer: Refer to endocrinologist for tight diabetic control before surgery
Incorrect:
Decline the surgery because the risk of failure is increased.
Start the patient on vitamin E supplementation 2000 IE daily 2 weeks before surgery.
Double his insulin dose on the morning of his surgery.
3. A 30-year-old man has a partial-thickness 4 4-cm abrasion on his right cheek. What should be the
best treatment?
Correct answer: Keep the wound bed moist with a moisture-retentive ointment
Incorrect:
Place a split-thickness skin graft.
Place a full-thickness skin graft.
Keep the wound dry to maximize reepithelialization.
4. A 50-year-old man sees you about a large wide scar on his neck. On inquiring, the patient states he
had a lymph node removed last year and this scar has grown bigger than the cyst was. What do you
counsel him about?
Correct answer: That this is a keloid and that multiple procedures along with steroid injections may
be required to excise it, but still there is no guarantee it will be removed completely
Incorrect:
That he most likely has a hypertrophic scar and that the likelihood is that this will not happen on further surgical
procedures.
That this is a keloid and that with vitamin E ointments it should resolve.
That this is a hypertrophic scar with completely go away with simple excision.
REFERENCES
1. Sipos P, Gyory H, Hagymasi K, et al. Special wound
healing methods used in Ancient Egypt and the
mythological background. World J Surg 2004;28:
2116.
2. Mogensen M, Morsy HA, Thrane L, et al. Morphology
and epidermal thickness of normal skin imaged by
optical coherence tomography. Dermatology 2008;
217(1):1420.
3. Ha RY, Nojima K, Adams WP Jr, et al. Analysis of
facial skin thickness: defining the relative thickness
index. Plast Reconstr Surg 2005;115(6):176973.
19.
20.
21.
22.
23.
24.
25.
26.
27.
97