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CLINICAL PRACTICE
Physiology of
Wound HealingBy Frances Strodtbeck, DNS, RNC, NNP
Abstract
Despite the emphasis placed on skin
care, hospitalized infants often
experience injury to their skin.
Although skin injuries vary, they have a
common innate mechanism for repair
and healing. Wound healing is a
physiologic process that involves a
series of sequential yet overlapping
stages. The first stage, hemostasis,
occurs immediately at the time of
injury. During hemostasis, a
provisional matrix seals the injury site
and initiates the process of wound
healing. The second stage,
inflammation, is triggered by a variety
of mediators released from injured
tissue cells and capillaries, activated
platelets and their cytokines, and the
by-products of hemostasis. During the
third stage, the wound surface is
covered with new skin and vascular and
structural integrity are restored as
granulation tissue fills the defect. The
final stage, remodeling, is responsible
for maturation of the granulation tissue
into mature connective tissue and/or
scar. A thorough understanding of
wound healing physiology is an
important prerequisite to providing care
that optimizes wound healing and
prevents unnecessary complications.
Many of the current wound care
practices are based on tradition rather
than scientific knowledge. As the
interface between the infant and the
environment, nurses are in an ideal
position to evaluate the soundness of
these wound care practices.Physiologic-based care strategies to
enhance wound healing are proposed.
Copyright c 2001 by
W.B. Saunders Company
From the Advanced Neonatal Nursing
Program, Baylor University, Louise Herrington
School of Nursing, Dallas, TX.
Address reprint requests to Frances Strodtbeck,
DNS, RNC, NNP, Associate Professor and
Coordinator, Advanced Neonatal Nursing
Program, Baylor University, Louise Herrington
School of Nursing, 3700 Worth St, Dallas,
TX 75246.
c2001 by W.B. Saunders Company1527-3369/01/0101-0555$35.00/0
doi: 10.1053/nbin.2001.23176
Despite the current emphasis placed on skin care, newborns and infants
who are hospitalized in the intensive care units often experience injury
to their skin. Although skin injuries vary in nature, they have a com-
mon innate mechanism for repair and healing. When triggered by an injury, this
mechanism is an elaborate cascade of physiologic events designed to repair and
ultimately heal the skin. Ironically, this process, whichis so important for survivalof the species, begins at birth with the severing of the umbilical cord. Although
the amount of scientific information regarding wound healing is increasing, there
is limited literature on wound healing in newborns and infants. This article de-
scribes thephysiologic process of wound healing, summarizes thecurrent state of
knowledge on wound healing, and discusses the implications for newborn/infant
skin care practices. A thorough understanding of wound healing and the factors
that promote or interfere with the process are essential to develop appropriate
clinical interventions for newborns and infants.
The first step in understanding wound healing is to clarify terminology. Ac-
cording to the Wound Healing Society, a wound is the disruption of normal
anatomic structure and function1 that can be classified into 1 of 2 categories
based on the nature of the repair process. These categories are acute and chronic
wounds. Acute wounds are typically tissue injuries caused by cuts or surgical in-cisions that complete the wound healing process within the expected time frame.
In contrast, chronic wounds are tissue injuries that heal sluggishly because of
repeated insults to the tissues and/or other underlying pathophysiology that in-
terferes with the expected time line and orderly sequence of wound healing.2,3
Wounds are also named by various descriptors reflective of the nature of the
injury, ie, burn, laceration, and so on. Table 1 provides a summary of common
definitions of wounds. Much of what is known about the physiology of wound
healing has been learned from the study of acute wound healing models.2
Healing is defined by the Wound Healing Society as a complex dynamic
process that results in the restoration of anatomic continuity and function. 1
Surgeons typically divide healing into categories based on the anticipated nature
of the repair process. The categories of healing by primary or secondary intention
and delayed primary repair are described in Table 2 and shown in Fig 1.
Wound Healing
Wound healing is a physiologic process involving a series of sequentialyet overlapping stages. There are anywhere from 3 to 5 stages of woundhealing, depending on how the various biologic mechanisms are linked. For the
purposes of this article, thegeneral stagesof wound healing describedby Schultz3
are used (Fig 2).
The first stage, hemostasis, occurs immediately at the time of injury and is
usually completed within hours. The second stage, inflammation, begins shortly
Newborn and Infant Nursing Reviews, Vol 1, No 1 (March), 2001: pp 4352 43
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44 Frances Strodtbeck
Table 1. Definitions of Wounds
Term Definition
Wound Disturbance in the normal skin anatomy and function; tissue injury resulting in the loss of continuity of epithelium
with or without the loss of underlying connective tissue 3
Acute wound Tissue injury that normally proceeds through an orderly and timely reparative process that results in sustained
restoration of anatomic and functional integrity 1
Chronic wound Tissue injury that fails to proceed through an orderly and timely reparative process to produce anatomic and
functional integrity or proceeds through the repair process without establishing a sustained anatomic and
functional result 1
Abrasion Loss of superficial skin (usually epithelium) that exposes nerve endings resulting in a painful injury; plasma and/or
blood loss similar to a burn can result from serious abrasions3
Contusion Severe laceration resulting in tissue loss and separation of tissue layers3
Incision Injury with no tissue loss and minimal tissue damage caused by a sharp object such as a scalpel or knife3
Laceration Nonsurgical injury in conjuction with some type of trauma, resulting in tissue loss and damage3
Ulcer Loss of an epithelial surface together with a variable degree of underlying connective tissue 3
after hemostasis and is usually completed within the first
24 to 72 hours after injury;4 however, it may last as long as
5 to 7 days after injury. Proliferation and repair, the third
stage, typically occurs 1 to 3 weeks after injury. The fourth
and final stage, remodeling, begins approximately 3 weeks
after injury and may take anywhere from months to sev-
eral years to achieve physiologic completion.2,57 Thus,
it is important to note that although the skin seems intact
withindays to severalweeksafter an injury, thetissue under-
neath is still vulnerable to damage as it undergoes the final
stages of wound healing. The reader should also remem-ber the time lines previously described are based on adult
models. Although there are no published newborn/infant
data, some investigators suggest children heal faster than
adults.78
Stage 1: Hemostasis
At the time of skin injury, bleeding usually occurs.
Not only does this bleeding serve to flush microorgan-
Table 2. Definitions of Healing
Term Definition
Healing Restoration of the normal structure and function of skin/tissue2
Primary intention Healing after a clean injury, such as an incision, in which there is minimal epithelialization and new tissue
needed to repair the skin defect; skin edges are approximated with sutures, staples, or adhesive, enabling
closure to occur quickly with minimal scarring7,19
Secondary
intention
Healing associated with a large and/or deep wound in which the tissue edges cannot be approximated; the
wound depth determines the degree of new tissue matrix and epidermal surface needed for complete
closure; this process is often lengthier than healing by primary intention and can be associated with
substantial scarring7,19
Delayed primary
(tertiary)
intention
Healing associated with wounds that are usually infected or dehisced surgical wounds; healing is promoted by
leaving the wound open for a prescribed period of time to treat the contamination or infection and to allow
for growth of new tissue before approximating the skin edges for a primary closure7,19
isms or antigens from the wound, but it also activates
hemostasis. Hemostasis is initiated by a variety of fac-
tors. Clotting factors released by injured skin cells acti-
vate the extrinsic clotting cascade.56 Platelet aggregation
and the exposureof collagenfrom the damaged skins initiate
the intrinsic clotting cascade and trigger platelet-mediated
vasoconstriction.6 This vasoconstriction prevents the fur-
ther loss of blood while the fibrin clot forms a temporary
seal over the injury site and prevents the influx of microor-
ganisms.
In addition to its protective role, hemostasis is criticalto successful wound healing.9 The fibrin clot is a provi-
sional matrix or scaffold that guides and supports the in-
flux of fibroblast and keratinocytes.10 This provisional ma-
trix is composed of fibrin and fibronectin. Fibronectin is a
multipurpose adhesion protein with an affinity for fibrin. It
circulates in blood and is also found in other tissues. Fi-
bronectinparticipates in wound healing in a variety of ways.
It serves as a chemoattractant for the migration of wound
repair cells and as a template for the deposition of collagen
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Physiology of Wound Healing 45
Fig 1. (A) Wound healing by primary intention, such as with a
surgical incision (left). Wound edges are pulled together and ap-
proximated with sutures, staples, or adhesive tapes, and healing
occurs mainly by connective tissue deposition. (B) Wound heal-
ing by secondary intention. Wound edges are not approximated,
and healing occurs by granulation tissue formation and contrac-
tion of the wound edges. (C) Wound healing by tertiary (delayed
primary) intention. Wound is kept open for several days. The su-
perficial wound edges arethen approximated, and thecenter of the
wound heals by granulation tissue formation. (Reprinted with per-
mission from Trott AT: Wounds and Lacerations [ed 2]. St Louis,
MO, Mosby, 1997)
fibers. It also participates in wound debridement by degrad-
ing extracellular matrix (ECM) debris and activating thephagocytic properties of macrophages.10
Platelet activation results in degranulation and the re-
lease of a variety of potent cytokines that induce the process
of tissue repair and activate additional immune defenses.
By attaching to exposed collagen fibers in the wound, ac-
tivated platelets also stimulate the production of new ECM
substances.10 The specific mechanisms mediated by these
cytokines include the recruitment of inflammatory cells to
the injury site (activation of the inflammatory response) and
the proliferation of new cells (epithelialization) and blood
vessels (angiogenesis) at the injury site. Because of the po-
tency of these cytokines and the specificity of their action
in the microenvironment of the injury site, minuscule quan-
tities of the cytokines are needed.2
One of the most interesting groups of cytokines pro-duced is platelet-mediated growth factors. These growth
factors are responsible for a variety of molecular processes
includingthe influx of fibroblasts and keratinocytes, the syn-
thesis of collagen and other ECM proteins, the regulation
of cell movement within the wound microenvironment, the
directed growth of new capillaries and vascular beds, and
the synthesis of enzymes used to reshape the newly formed
connective tissue.11,12 A listing of the specific growth fac-
tors and their functions can be found in Table 3.
Stage 2: Inflammation
The second stage of wound healing is inflammation. Theinflammatory response is triggered by a variety of media-
tors released from injured tissue cells and capillaries, acti-
vated platelets and their cytokines, and the by-products of
hemostasis. Within minutes after the injury, neutrophils ar-
rive to contain any microorganisms present in the wound.2,9
Neutrophils also initiate wound repair by activating local fi-
broblasts and epithelial cells.13 Although other white cells,
including monocytes, lymphocytes, and plasma cells, mi-
grate to the injury site, neutrophils predominant for the first
few days and then disappear unless the wound becomes
infected.2,6 In the presence of infection, neutrophil infiltra-
tion continues until the infection is controlled.
In the absence of infection, the existing monocytesdiffer-
entiate into macrophages and become the major phagocytic
cellattheinjurysite.5 Macrophageinfiltrationpredominates
for the remainder of the wound healing process. In addition
to ingesting surviving microorganisms, dead neutrophils,
the fibrin clot, and other cellular debris, macrophages syn-
thesize nitric oxide and secrete cytokines to initiate wound
repair. Although the exact nature of nitric oxides involve-
ment in wound healing is unknown, animal studies sug-
gest an important role in the regulation of keratinocytes, ie,
low concentrations of nitric oxide increased cell prolifera-
tion, whereas high concentrations resulted in increased cell
differentiation.14,15
According to Haas,4 the macrophage is the transition
cell between wound inflammation and wound repair be-
cause of its essential role in wound healing. As the need for
immune defense diminishes, macrophages take over regu-
lation of the wound healing process. The importance of this
role is underscored by studies that have shown that wounds
can heal normally in the absence of neutrophils but not in
the absence of macrophages.16
Like the platelet, the macrophage synthesizes a variety
of cytokines including growth factors involved in the migra-
tion, proliferation, and organization of new connective tis-
sue and vascular beds within the wound. Unlike the platelet
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46 Frances Strodtbeck
Fig 2. Temporal relationship between the multiple processes occurring in dermal wound healing. (Reprinted with permission 6)
that releases stored cytokines, the macrophage is able to
synthesize and secrete cytokines over time, assuring con-
tinuation of the process of tissue repair.2,11,12
Macrophages also produce special enzymes called ma-
trix metalloproteinases or metalloproteases (MMPs).5 To
date, more than 20 unique MMPs have been identified.16
One of the best-studied enzymes is collagenase, which plays
a pivotal role in wound debridement and the shaping of new
connective tissue.
Another important mechanism in the inflammatory stage
of wound healing is activation of vasoactive substancessuch
as serotonin, bradykinin, prostaglandins, and histamine.2,4
Table 3. Platelet-Mediated Growth Factors Involved in Wound Healing
Cytokine Purpose/Function
Epidermal growth factors (EGF) Mitosis and migration of keratinocytes; stimulates wound re-epithelialization;
angiogenesis
Fibroblast growth factor (FGF) Mitosis and migration of keratinocytes and fibroblasts; stimulates collagen formation;
angiogenesis
Insulin-like growth factors (IGF-1, IGF-2) Mitosis of keratinocytes and fibroblasts
Keratinocyte growth factor (KGF) Mitosis of keratinocytes; activation of monocytes
Platelet-derived growth factor (PDGF) Chemoattractant for fibroblasts and other cells; cell proliferation; wound contraction
Transforming growth factor- (TGF-) Mitosis and migration of keratinocytes; regulation of inflammatory cells
Transforming growth factor- (TGF-) Chemoattractant for fibroblasts and macrophages; migration of keratinocytes; fibroblast
matrix synthesis and remodeling
Data from.5,911
These substances increase permeability of endothelium
within the injury site and increase perfusion to the site. In-
creased permeability facilitates infiltration by immune and
repair cells, whereas increased circulation increases oxygen
delivery. As a consequence, the temperature at the injury site
increases and fluid begins to leak into the wound. Although
clinically this results in skin erythema and edema, the
warm, moist microenvironment created within the wound is
essential for the next stage of healing.2 At the end of the in-
flammation stage of wound healing, bleeding is controlled
and the wound bed is clean. This creates the perfect envi-
ronment for the next stage of cell proliferation and repair.
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Physiology of Wound Healing 47
Stage 3: Proliferation and Repair
Thespecific mechanisms of stage 3 areaimed at coveringthe wound surface with new skin (re-epithelization), restor-
ing vascularintegrity to the region (neovascularization), and
repairingthe structureintegrity of thetissue defectby filling
it with new connective tissue (granulation).2 Wound (ten-
sile) strength begins to develop during this stage. Key cells
for these processes are the fibroblast and keratinocyte.
The warm, moist microenvironment of the wound also
facilitates proliferation and repair. The leaked fluid or exu-
date is rich in cytokines that stimulate new tissue growth.
Shortly after the injury occurs, hypoxia and acidosis de-
velopwithin thewoundbed as thepartialpressure of oxygen
decreases to around 10 mm Hg, the partial pressure of car-
bon dioxide increases to 80 mm Hg, and the pH approaches6.8.18 This leads to an increase in lactate or lactic acid. Al-
though at first glance it would seem that hypoxia and acido-
sis are counterproductive to healing, these processes stimu-
late angiogenesis (growth of new blood vessels) and colla-
gen synthesis. Because lactate modulates the concentration
of a variety of enzymes involved in cell energy metabolism
and transcription, increased lactate levels stimulate collagen
synthesis within the wound. The rate of collagen secretion
is partially governed by oxygen delivery to the newly de-
veloping tissue. This in turn influences the tensile strength
of the repair.18
Neovascularization
Essential parts of any repair process are the availability of a
steadysupply of nutrientsand an intactdelivery system. The
process of restoring the vascular network is called neovas-
cularization or angiogenesis. Neovascularization is stimu-
lated by growthfactors andtissue hypoxia. At thestart of the
wound healing process, the most viable parts of the wound
arethose with accessto a vascularsupplythewound edges
and the parts in contact with the underlying dermal vascular
bed.19 This creates a hypoxic gradient between the avascu-
lar wound center and the vascularized wound borders.2 In-
creased endothelial permeability allows nutrients to escapefrom the intact vascular bed into the interstitium and injury
site. This creates a nutrient-rich microenvironment that sus-
tains the developing repair process until neovascularization
can occur.
Closure of the wound surface is necessary to create a
hypoxic wound environment. The fibrin clot formed during
hemostasis provides a temporary cover that is eventually re-
placed by new epidermal cells. This creates a closed system
in which angiogenesis can proceed.10 Hypoxia is thought to
induce macrophages into secreting angiogenic growth fac-
tors. Lactic acidosis also stimulates angiogenesis.18 Platelet
and macrophage-derived growth factors, such as fibroblast
growth factor and vascular endothelial growth factor, are re-
leased by endothelial cells and stimulate angiogenesis along
the wound edges.9 New blood vessels bud or sprout fromintact vessels in the underlying dermis.19 The new capillary
buds join to form capillary loops thereby establishing blood
flow within the wound.10 New sprouts or buds extend from
the capillary loops further into the wound environment. The
process of arborization is thus stimulated by hypoxia within
the wound environment and results in the growth of new
vessels throughout the wound.
Another essential requirement of neovascularization is
the formation of an appropriate ECM with an adequate
supply of oxygen. Collagen deposition is critical for aor-
tic endothelial cell migration.10 Several key enzymes that
are oxygen dependent control collagen synthesis. Because
these rate-limiting enzymes extract about 1 mL of oxygenper 100 mL of blood,18 oxygen delivery to the developing
tissueis more critical than thetotalamount of oxygen. Thus,
perfusion to the site of injury is the major determinant of
oxygenation.10
Re-epithelization
Re-epithelization of a wound occurs when keratinocytes
completely cover the surface of the skin defect. As the
largest group of epithelial cells within the epidermis, ker-
atinocytes along the wound edges undergo intense mi-
totic activity. Keratinocytes, stimulated by locally released
growth factors, proliferate and begin their migration across
the wound bed within 12 to 24 hours after injury.19,20 Be-
cause the site of proliferation is usually proximal to the
injury, the new keratinocytes must migrate to the repair
site. Migration requires a fluid environment2 and involves a
complex series of steps controlled by a chemotactic gradi-
ent generated by various growth factors. In the absence of a
fluid surface, the keratinocyte secretes proteolytic enzymes
that enable it to burrow downward to find the necessary
moisture for migration (Fig 3).2,21
The first step of migration involves separation of the
keratinocytes from each other and their anchors to the cellbasement membrane.22 The migrating keratinocyte then un-
dergoes transformation by elongating itself in the direc-
tion growth is needed. The leading edge of the elongated
keratinocyte attaches to a new spot in the wound bed. The
cell then contracts, pulling itself forward across the wound
surface. This process is repeated until the migrating cells
from opposing sides of the wound touch each other. At the
pointof contact, migrationceasesin a process known as con-
tact inhibition.22,23 Another process used for keratinocyte
migration is leapfrogging (Fig 4). Leapfrogging occurs
when a single cell moves only 2 or 3 cell lengths and then
stops, allowing consecutive cells to climb over.2
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48 Frances Strodtbeck
Fig 3. Diagram of migration of epidermal cells in (A) moist environment and (B) dry environment. (Reprinted with permission 2)
As keratinocytes proliferate and migrate across the
wound, they also participate in shaping the ECM by ex-
pressing surface markers that enhance migration across the
matrix.10 Supporting structures are selectively degraded
and resynthesized to provide temporary anchors during
the migratory phase. Once migration is complete, the ker-
atinocytes stabilizethemselves by forming firm attachments
to each other and the new basement membrane.10,23 Migra-
tion proceeds from the wound edges towards the center in
a centripetal manner.9,10
When the skin surface is completely covered with new
epidermal cells, the wound is considered closed. Early clo-
sure of an open wound with a viable epidermis is essential
because it induces remodeling of the underlying tissue. The
chance of developing hypertrophic scar tissue is also greatly
reduced by early wound closure.19
Fig4. Epidermalcell migrationvia development of pseudopod and
leapfrogging. (Reprinted with permission2)
Granulation
The third and final mechanism of proliferation and repair is
the development of granulation tissue. Granulation tissue,
a transitional substance that replaces the fibrin/fibronectin
matrix, begins to appearabout4 days after injury.10,19 Gran-
ulation occursas thefibrinclot scaffoldis replaced with new
tissue rich in hyaluronan (hyaluronic acid), fibronectin, and
other ECM compounds. Because granulation tissue is very
active metabolically and supports the proliferation of a va-
riety of cells and proteins, it is also highly vascular.19 This
accounts for its classic pinkish-red appearance.
The predominant cell type found in granulation tissue is
the fibroblast.19 Fibroblasts are dermal cells that produce
collagen and numerous other substances that comprise the
ECM. ECM is composed of substances that promote adhe-
sion and migration (fibronectin); glycoaminoglycans that
promote tissue hydration (hyaluronan); proteoglycans or
matrix proteins that are involved in the regulation, migra-
tion, storage, and expression of a variety of substances in-
cluding growth factors, enzymes, and coagulation proteins
(chondroitin sulfate); and glycoproteins that provide tissuestrength and resiliency (collagens, elastin).10,24 Fibroblast
migration and proliferation are triggered by signals from
platelet-derived growth factor, transforming growth factor,
fibroblast growth factor, and complement C5a released by
activated cells of the inflammatory response.19
The influx of fibroblasts causes the provisional matrix
of fibrin/fibronectin to be degraded and replaced with a
new matrix. After migration to the wound, fibroblasts begin
to synthesize the proteins hyaluronan and fibronectin.10,19
This new matrix is composed of fibronectin and collagen
that provides a scaffold for cell migration and organization,
hyaluronan that facilitates migration by providing a low
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Physiology of Wound Healing 49
impedance medium, and macrophages and other substances
that provide essential cytokines.10
Normal dermal fibroblasts and the fibroblasts involvedin theformation of granulation tissue differin both structure
and function. Wound fibroblasts tend to be involved in col-
lagen synthesis rather than proliferation.2 These fibroblasts
produce and release proteoglycans, glycosaminoglycans,
and collagen.6 They also participate in theprocess of wound
contraction after differentiation into myofibroblasts.25
Differentiated fibroblasts contain contractile proteins
such as actin.6 Myofibroblasts are arranged in densely
packed groups. This arrangement, in conjunction with
their special contractile properties, allows the myofibrob-
last to pull wound edges together through the process of
contraction.25 Contraction decreases healing time because
it decreases the size of the wound and reduces the amount ofECM needed to repair the defect.26 Contraction also facili-
tates re-epithelization by shortening the distance migrating
keratinocytes must travel.10
The structure and composition of granulation tissue un-
dergoes constant change as it matures. Although collagen
becomes the predominant protein, there are at least 19 dif-
ferent types of collagen.24 The type of collagen present in
a tissue varies with the tissue. For example, skin collagen
is 80% type I and 20% type III. 19,24
Thenew granulation tissue contains type I, III, andV col-
lagen fibers.24 Thirty percent of the collagen is type III col-
lagen, which does not contribute to restoring tensile strength
in the wound.19 At 3 weeks after injury, the healing wound
has approximately 20% of its final strength.2,19
Stage 4: Remodeling
The final stage of wound healing is remodeling or mat-
uration of the granulation tissue into mature connective tis-
sue and/or scar. The wound also develops its final strength
during this stage of wound healing.25 The key cells for re-
modeling are macrophages and fibroblasts. ECM reshaping
by cross-linking collagens, cell maturation, and program
cell death or apoptosis are the mechanisms used in woundremodeling.10 Collagen synthesis peaks around 5 days af-
ter injury but continues for weeks or months. 2 During this
time, collagen andECM tissue continue to be deposited into
the wound, whereas the developing connective tissue is re-
shaped by cell maturation and apoptosis. Although wound
strength increases, it never achieves more than 80% of the
preinjury strength.2,5,27
Wound remodeling begins at different times in different
regions. ECM-bound growth factors and MMPs are acti-
vated by macrophages and fibroblasts, resulting in degrada-
tion of the matrix and differentiation of cells.28 Collagen is
first released in precursorformas a triplehelix protein called
procollagen. Procollagen is then formed into fibers that are
arranged in parallel fashion and cross-linked to form thicker
and stronger strands.2 This process converts the loose gran-ulation tissue matrix into a stable ECM.3 There are substan-
tial differences between the repaired tissue and noninjured
skin. The new connective tissue is not as well anchored to
the underlying connective tissue matrix and is thicker than
normal skin.19
During this time, fibronectin and hyaluronan are re-
placed, collagen bundles grow in size and strength, neovas-
cularization ceases, and metabolic activity within the ECM
declines. Type III collagen decreases from 30% to 10%,
with the net result a much stronger tissue.19 The density of
cells, such as macrophages, keratinocytes, fibroblasts, and
myofibroblasts, is reduced by apoptosis.10,19 Keratinocytes
are the first cells to undergo programmed cell death; my-ofibroblasts are the second.10 Remodeling is thus a balance
between the synthesis of new collagen and the degradation
of old.4 Remodeling is regulated by fibroblasts through the
synthesis of ECM components and MMPs that control cell
differentiation. 28 As the wound healing process is switched
off, the new connective tissue matures and changes from
pinkish-red to a white color.7
Clinical Implications
Although there is a paucity of literature on wound heal-
ing in newborns/infants, there is no reason to ignore
scientific knowledge when developing management strate-
gies for newbornsand infants with skin injuries. A thorough
understanding of wound healing physiology is an important
prerequisite to providing care that optimizes wound heal-
ing and prevents unnecessary complications. Many of the
current wound care practices are based on tradition and
may not be grounded in scientific soundness. As the inter-
face between the infant and the environment, nurses are in
an ideal position to evaluate the soundness of wound care
practices. Advanced-practice nurses have the added advan-
tage of being able to bridge medical and nursing care and
are in an ideal position to direct changes in wound manage-ment care.
Obviously, the most important wound management ac-
tivity is the prevention of skin injury; however, that is not
always possible. Some infants require procedures, such as
surgery, thatnecessitatean incision.Other infants may expe-
rience extravasation of intravenous fluids, resulting in skin
injury. The clinician who understands the science of wound
healing will be able to prevent complications and maximize
the infants ability to heal.
Because preventing skin injury is not always realistic,
it is important to provide care that optimizes the infants
ability to heal him/herself. Care should be focused on
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50 Frances Strodtbeck
Table 4. Strategies to Promote Wound Healing in Newborns/Infants
Wound Healing
Care Strategy Event Trageted Scientific Rationale
Maintain normal serum
calcium levels
Collagen maturation; wound
contraction
Actin-myosin contractility is calcium dependent39
Maintain normal perfusion Metabolic activities within
the wound
microenvironment
Maximizes oxygen delivery to the wound bed
Maintain adequate
oxygenation
Collagen synthesis;
fibroblast proliferation;
keratinocyte mitosis
Collagen synthesis and secretion depends on oxygen-dependent
enzyme reactions19; increases tissue resistance to infection2
Maintain iron stores and/or
provide ferrous iron
Collagen synthesis and
remodeling
Ferrous iron is a co-factor for collagen hydroxylation reactions19
Cover injuries with an
occlusive hydrocolloid
dressing
Keratinocyte migration;
sequestering of growth
factors
The hydrocolloid dressing provides a temporary cover under which
wound exudate can collect; this allows the wound bed to be bathed
with growth-factor rich fluid that facilitates keratinocyte migration;
the application of an occlusive hydrocolloid may decrease the risk
of wound infection4043
Keep the infant in a neutral
thermal environment
Inflammatory cell activity;
Leukocyte activity
Hypothermia decreases leukocyte mitotic activity44; the ideal wound
temperature is 37C44
Maintain renal function Production of granulation
tissue; Fibroblast and
keratinocyte proliferation
Animal data shows that acute renal failure leads to inadequate
granulation tissue production4547; chronic renal failure is
associated with decreases in plasma fibronectin concentration37
Prevent sepsis/infections Inflammatory response;
collagen synthesis;
epithelialization
Infection prolongs the inflammatory process, which delays wound
healing; prolonged exposure to inflammatory cytokines also
produces tissue damage2
Avoid the use ofcorticosteroids
Every aspect of woundhealing
Corticosteroids have a substantial impact on every stage of woundhealing; they reduce macrophage migration, suppress the
inflammatory response decrease keratinocyte and fibroblast
proliferation, impair capillary budding, decrease ECM production,
decrease protein synthesis, delay epithelialization, and block the
release of vasoactive factors2,6,48,49
Maximize protein in
parenteral and/or enteral
nutrition
Collagen synthesis; wound
contraction and
remodeling
Additional protein is needed to meet the demands of wound
healing49,50
Provide vitamins A, and C
and B-complex vitamins
(thiamine, niacin,
riboflavin, folate, B12)
Epithelialization; collagen
synthesis; cell metabolism
Vitamin A promotes epithelial integrity; the B-complex vitamins are
important for anabolic reactions such as wound healing; vitamin C
is a co-factor for collagen synthesis and is important for normal
immune function49,50
Provide zinc and copper Collagen synthesis Zinc is a co-factor for collagen synthesis,19 epithelialization, and
fibroblast proliferation6 Copper is a co-factor for collagencross-linking reactions6
Maintain euvolemia Tissue oxygenation Normal perfusion is needed to maintain the wound microenvironment
and the developing ECM51
Provide adequate pain
management
Wound perfusion; all aspects
of wound healing
Connective tissue perfusion is sensitive to autonomic nervous
activity18; pain results in catecholamine release that can lead to
vasoconstriction and impaired wound perfusion,2 pain also
stimulates corticosteroid release that can interfere with wound
healing
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Physiology of Wound Healing 51
facilitating wound healing and preventing complications of
existing wounds. Physiologic-based care strategies to en-
hance wound healing are provided in Table 4.Two strategies thatdeservespecialattention are the use of
corticosteroids and wound dressings. Corticosteroids have
a profound suppressive effect on the inflammatory response
and affect every aspect of wound healing. The use of cor-
ticosteroids should be avoided in infants with serious skin
injuries and surgical infants. Animal data from Sandberg29
suggest that delaying the use of corticosteroids until after
the inflammatory stage may decrease the negative conse-
quences on wound healing. Simultaneous administration of
vitamin A during corticosteroid therapy has been shown
also to reverse the effects of steroids on wound healing.30,31
The type of wound dressing has been a controversial
subject for many years. Wound dressing preferences tendto be based on prior experience and tradition rather than
scientific data. Many clinicians advocate the use of gauze
or air-treated wounds. Allowing wounds to dry out causes
the repair process to stop.7 In a study comparing the use
of gauze dressings or air-treated wounds with the use of a
moist dressing, Eaglstein32 noted a 40% reduction in heal-
ing in the gauze or air-treated wounds. Other studies have
shown that moisture-retentive, hydrocolloid dressings pro-
mote wound healing by increasing fibrinolysis and autolysis
of necrotic tissue, facilitate the release of growth factors, re-
duce thetime to heal, andpromote angiogenesis.3335 Other
advantages reported with this type of dressing are decreases
in pain, trauma to the wound from dressing changes, the
risk of wound infection, the risk for nosocomial infections
caused by airborne transmission of microorganisms, and the
cost of care.7,21
Other studies pose intriguing questions regarding wound
management in newborns and infants. A study from Japan
showed increased fibroblast growth in cultured human cells
and venous leg ulcers in adults treated with intermittent
radiant warming.36 This raises the question, What is the
impact on wound healing when infants live in a heated in-
cubator or on a radiant warmer? Does humidification of the
environment contribute to wound healing? Mulder et al37
discuss a number of studies evaluating the impact of jaun-dice on wound healing; their conclusion is jaundiceclearly
has the potential to impair wound healing. If this is indeed
true, What is the impact of hyperbilirubinemia on wound
healing in infants? Other studies shown that theamino acids
arginine and glutamine promote wound healing by improv-
ing collagen synthesis.38,39 Should newborns and infants
with substantial wounds receive arginine and/or glutamine
supplementation? Although these questions remain unan-
swered, it is clear that there are many areas for knowledge
development in the understanding of wound healing in the
infant population.
Conclusion
Wound healing is a fascinating biologic event essentialfor human survival. Although many of the physio-logic processes have been studied in animal and adult mod-
els, little information is available regarding wound healing
in infants. Because of the immaturity of their skin, many
hospitalized infants are at high risk for skin injuries. Other
infants experience skin injury after surgery and/or inva-
sive procedures. It is essential that clinicians understand
the physiology of wound healing so they can provide com-
petent care that optimizes the infants ability to heal and
prevents further injury and/or complications.
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