CLINICAL PRACTICE

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 rst 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, inammation, 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 lls the defect. The nal 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 scientic 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. c 2001 by W.B. Saunders Company 1527-3369/01/0101-0555$35.00/0 doi: 10.1053/nbin.2001.23176

Physiology of Wound Healing

By Frances Strodtbeck, DNS, RNC, NNP
espite 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 common 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, which is so important for survival of the species, begins at birth with the severing of the umbilical cord. Although the amount of scientic information regarding wound healing is increasing, there is limited literature on wound healing in newborns and infants. This article describes the physiologic process of wound healing, summarizes the current 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 rst step in understanding wound healing is to clarify terminology. According to the Wound Healing Society, a wound is the disruption of normal anatomic structure and function1 that can be classied 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 incisions 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 interferes with the expected time line and orderly sequence of wound healing.2,3 Wounds are also named by various descriptors reective of the nature of the injury, ie, burn, laceration, and so on. Table 1 provides a summary of common denitions 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 dened 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

ound healing is a physiologic process involving a series of sequential yet overlapping stages. There are anywhere from 3 to 5 stages of wound healing, depending on how the various biologic mechanisms are linked. For the purposes of this article, the general stages of wound healing described by Schultz3 are used (Fig 2). The rst stage, hemostasis, occurs immediately at the time of injury and is usually completed within hours. The second stage, inammation, begins shortly
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Table 1. Denitions of Wounds Term Wound Acute wound Chronic wound Denition 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 Tissue injury that normally proceeds through an orderly and timely reparative process that results in sustained restoration of anatomic and functional integrity 1 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 Loss of supercial 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 Severe laceration resulting in tissue loss and separation of tissue layers3 Injury with no tissue loss and minimal tissue damage caused by a sharp object such as a scalpel or knife3 Nonsurgical injury in conjuction with some type of trauma, resulting in tissue loss and damage3 Loss of an epithelial surface together with a variable degree of underlying connective tissue 3

Abrasion Contusion Incision Laceration Ulcer

after hemostasis and is usually completed within the rst 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 nal stage, remodeling, begins approximately 3 weeks after injury and may take anywhere from months to several years to achieve physiologic completion.2,57 Thus, it is important to note that although the skin seems intact within days to several weeks after an injury, the tissue underneath is still vulnerable to damage as it undergoes the nal stages of wound healing. The reader should also remember 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 ush microorgan-

isms or antigens from the wound, but it also activates hemostasis. Hemostasis is initiated by a variety of factors. Clotting factors released by injured skin cells activate the extrinsic clotting cascade.56 Platelet aggregation and the exposure of collagen from the damaged skins initiate the intrinsic clotting cascade and trigger platelet-mediated vasoconstriction.6 This vasoconstriction prevents the further loss of blood while the brin clot forms a temporary seal over the injury site and prevents the inux of microorganisms. In addition to its protective role, hemostasis is critical to successful wound healing.9 The brin clot is a provisional matrix or scaffold that guides and supports the inux of broblast and keratinocytes.10 This provisional matrix is composed of brin and bronectin. Fibronectin is a multipurpose adhesion protein with an afnity for brin. It circulates in blood and is also found in other tissues. Fibronectin participates 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

Table 2. Denitions of Healing Term Healing Primary intention Denition Restoration of the normal structure and function of skin/tissue2 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 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 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

Secondary intention

Delayed primary (tertiary) intention

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in the microenvironment of the injury site, minuscule quantities of the cytokines are needed.2 One of the most interesting groups of cytokines produced is platelet-mediated growth factors. These growth factors are responsible for a variety of molecular processes including the inux of broblasts and keratinocytes, the synthesis 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 specic growth factors and their functions can be found in Table 3. Stage 2: Inammation The second stage of wound healing is inammation. The inammatory response 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. Within minutes after the injury, neutrophils arrive to contain any microorganisms present in the wound.2,9 Neutrophils also initiate wound repair by activating local broblasts and epithelial cells.13 Although other white cells, including monocytes, lymphocytes, and plasma cells, migrate to the injury site, neutrophils predominant for the rst few days and then disappear unless the wound becomes infected.2,6 In the presence of infection, neutrophil inltration continues until the infection is controlled. In the absence of infection, the existing monocytes differentiate into macrophages and become the major phagocytic cell at the injury site.5 Macrophage inltration predominates for the remainder of the wound healing process. In addition to ingesting surviving microorganisms, dead neutrophils, the brin clot, and other cellular debris, macrophages synthesize nitric oxide and secrete cytokines to initiate wound repair. Although the exact nature of nitric oxides involvement in wound healing is unknown, animal studies suggest an important role in the regulation of keratinocytes, ie, low concentrations of nitric oxide increased cell proliferation, whereas high concentrations resulted in increased cell differentiation.14,15 According to Haas,4 the macrophage is the transition cell between wound inammation and wound repair because of its essential role in wound healing. As the need for immune defense diminishes, macrophages take over regulation 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 migration, proliferation, and organization of new connective tissue and vascular beds within the wound. Unlike the platelet

Fig 1. (A) Wound healing by primary intention, such as with a surgical incision (left). Wound edges are pulled together and approximated with sutures, staples, or adhesive tapes, and healing occurs mainly by connective tissue deposition. (B) Wound healing by secondary intention. Wound edges are not approximated, and healing occurs by granulation tissue formation and contraction of the wound edges. (C) Wound healing by tertiary (delayed primary) intention. Wound is kept open for several days. The supercial wound edges are then approximated, and the center of the wound heals by granulation tissue formation. (Reprinted with permission from Trott AT: Wounds and Lacerations [ed 2]. St Louis, MO, Mosby, 1997)

bers. It also participates in wound debridement by degrading extracellular matrix (ECM) debris and activating the phagocytic properties of macrophages.10 Platelet activation results in degranulation and the release of a variety of potent cytokines that induce the process of tissue repair and activate additional immune defenses. By attaching to exposed collagen bers in the wound, activated platelets also stimulate the production of new ECM substances.10 The specic mechanisms mediated by these cytokines include the recruitment of inammatory cells to the injury site (activation of the inammatory response) and the proliferation of new cells (epithelialization) and blood vessels (angiogenesis) at the injury site. Because of the potency of these cytokines and the specicity of their action

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Fig 2. Temporal relationship between the multiple processes occurring in dermal wound healing. (Reprinted with permission6 )

that releases stored cytokines, the macrophage is able to synthesize and secrete cytokines over time, assuring continuation of the process of tissue repair.2,11,12 Macrophages also produce special enzymes called matrix metalloproteinases or metalloproteases (MMPs).5 To date, more than 20 unique MMPs have been identied.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 inammatory stage of wound healing is activation of vasoactive substances such as serotonin, bradykinin, prostaglandins, and histamine.2,4

These substances increase permeability of endothelium within the injury site and increase perfusion to the site. Increased permeability facilitates inltration by immune and repair cells, whereas increased circulation increases oxygen delivery. As a consequence, the temperature at the injury site increases and uid 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 inammation stage of wound healing, bleeding is controlled and the wound bed is clean. This creates the perfect environment for the next stage of cell proliferation and repair.

Table 3. Platelet-Mediated Growth Factors Involved in Wound Healing Cytokine Epidermal growth factors (EGF) Fibroblast growth factor (FGF) Insulin-like growth factors (IGF-1, IGF-2) Keratinocyte growth factor (KGF) Platelet-derived growth factor (PDGF) Transforming growth factor- (TGF-) Transforming growth factor- (TGF-) Data from.5,911 Purpose/Function Mitosis and migration of keratinocytes; stimulates wound re-epithelialization; angiogenesis Mitosis and migration of keratinocytes and broblasts; stimulates collagen formation; angiogenesis Mitosis of keratinocytes and broblasts Mitosis of keratinocytes; activation of monocytes Chemoattractant for broblasts and other cells; cell proliferation; wound contraction Mitosis and migration of keratinocytes; regulation of inammatory cells Chemoattractant for broblasts and macrophages; migration of keratinocytes; broblast matrix synthesis and remodeling

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Stage 3: Proliferation and Repair The specic mechanisms of stage 3 are aimed at covering the wound surface with new skin (re-epithelization), restoring vascular integrity to the region (neovascularization), and repairing the structure integrity of the tissue defect by lling it with new connective tissue (granulation).2 Wound (tensile) strength begins to develop during this stage. Key cells for these processes are the broblast and keratinocyte. The warm, moist microenvironment of the wound also facilitates proliferation and repair. The leaked uid or exudate is rich in cytokines that stimulate new tissue growth. Shortly after the injury occurs, hypoxia and acidosis develop within the wound bed as the partial pressure of oxygen decreases to around 10 mm Hg, the partial pressure of carbon dioxide increases to 80 mm Hg, and the pH approaches 6.8.18 This leads to an increase in lactate or lactic acid. Although at rst glance it would seem that hypoxia and acidosis are counterproductive to healing, these processes stimulate angiogenesis (growth of new blood vessels) and collagen 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 developing tissue. This in turn inuences the tensile strength of the repair.18 Neovascularization Essential parts of any repair process are the availability of a steady supply of nutrients and an intact delivery system. The process of restoring the vascular network is called neovascularization or angiogenesis. Neovascularization is stimulated by growth factors and tissue hypoxia. At the start of the wound healing process, the most viable parts of the wound are those with access to a vascular supplythe wound edges and the parts in contact with the underlying dermal vascular bed.19 This creates a hypoxic gradient between the avascular wound center and the vascularized wound borders.2 Increased endothelial permeability allows nutrients to escape from the intact vascular bed into the interstitium and injury site. This creates a nutrient-rich microenvironment that sustains the developing repair process until neovascularization can occur. Closure of the wound surface is necessary to create a hypoxic wound environment. The brin clot formed during hemostasis provides a temporary cover that is eventually replaced 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 factors. Lactic acidosis also stimulates angiogenesis.18 Platelet and macrophage-derived growth factors, such as broblast

growth factor and vascular endothelial growth factor, are released by endothelial cells and stimulate angiogenesis along the wound edges.9 New blood vessels bud or sprout from intact vessels in the underlying dermis.19 The new capillary buds join to form capillary loops thereby establishing blood ow 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 aortic endothelial cell migration.10 Several key enzymes that are oxygen dependent control collagen synthesis. Because these rate-limiting enzymes extract about 1 mL of oxygen per 100 mL of blood,18 oxygen delivery to the developing tissue is more critical than the total amount 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, keratinocytes along the wound edges undergo intense mitotic 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 Because the site of proliferation is usually proximal to the injury, the new keratinocytes must migrate to the repair site. Migration requires a uid environment2 and involves a complex series of steps controlled by a chemotactic gradient generated by various growth factors. In the absence of a uid surface, the keratinocyte secretes proteolytic enzymes that enable it to burrow downward to nd the necessary moisture for migration (Fig 3).2,21 The rst step of migration involves separation of the keratinocytes from each other and their anchors to the cell basement membrane.22 The migrating keratinocyte then undergoes transformation by elongating itself in the direction 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 point of contact, migration ceases in a process known as contact 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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Fig 3. Diagram of migration of epidermal cells in (A) moist environment and (B) dry environment. (Reprinted with permission2 )

As keratinocytes proliferate and migrate across the wound, they also participate in shaping the ECM by expressing 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 keratinocytes stabilize themselves by forming rm attachments to each other and the new basement membrane.10,23 Migration 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 closure 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

Granulation The third and nal mechanism of proliferation and repair is the development of granulation tissue. Granulation tissue, a transitional substance that replaces the brin/bronectin matrix, begins to appear about 4 days after injury.10,19 Granulation occurs as the brin clot scaffold is replaced with new tissue rich in hyaluronan (hyaluronic acid), bronectin, and other ECM compounds. Because granulation tissue is very active metabolically and supports the proliferation of a variety 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 broblast.19 Fibroblasts are dermal cells that produce collagen and numerous other substances that comprise the ECM. ECM is composed of substances that promote adhesion and migration (bronectin); glycoaminoglycans that promote tissue hydration (hyaluronan); proteoglycans or matrix proteins that are involved in the regulation, migration, storage, and expression of a variety of substances including growth factors, enzymes, and coagulation proteins (chondroitin sulfate); and glycoproteins that provide tissue strength and resiliency (collagens, elastin).10,24 Fibroblast migration and proliferation are triggered by signals from platelet-derived growth factor, transforming growth factor, broblast growth factor, and complement C5a released by activated cells of the inammatory response.19 The inux of broblasts causes the provisional matrix of brin/bronectin to be degraded and replaced with a new matrix. After migration to the wound, broblasts begin to synthesize the proteins hyaluronan and bronectin.10,19 This new matrix is composed of bronectin and collagen that provides a scaffold for cell migration and organization, hyaluronan that facilitates migration by providing a low

Fig 4. Epidermal cell migration via development of pseudopod and leapfrogging. (Reprinted with permission2 )

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impedance medium, and macrophages and other substances that provide essential cytokines.10 Normal dermal broblasts and the broblasts involved in the formation of granulation tissue differ in both structure and function. Wound broblasts tend to be involved in collagen synthesis rather than proliferation.2 These broblasts produce and release proteoglycans, glycosaminoglycans, and collagen.6 They also participate in the process of wound contraction after differentiation into myobroblasts.25 Differentiated broblasts contain contractile proteins such as actin.6 Myobroblasts are arranged in densely packed groups. This arrangement, in conjunction with their special contractile properties, allows the myobroblast 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 of ECM needed to repair the defect.26 Contraction also facilitates re-epithelization by shortening the distance migrating keratinocytes must travel.10 The structure and composition of granulation tissue undergoes constant change as it matures. Although collagen becomes the predominant protein, there are at least 19 different 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 The new granulation tissue contains type I, III, and V collagen bers.24 Thirty percent of the collagen is type III collagen, 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 nal strength.2,19

procollagen. Procollagen is then formed into bers that are arranged in parallel fashion and cross-linked to form thicker and stronger strands.2 This process converts the loose granulation tissue matrix into a stable ECM.3 There are substantial 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, bronectin and hyaluronan are replaced, collagen bundles grow in size and strength, neovascularization 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, broblasts, and myobroblasts, is reduced by apoptosis.10,19 Keratinocytes are the rst cells to undergo programmed cell death; myobroblasts 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 broblasts 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
lthough there is a paucity of literature on wound healing in newborns/infants, there is no reason to ignore scientic knowledge when developing management strategies for newborns and infants with skin injuries. 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 and may not be grounded in scientic soundness. As the interface 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 advantage of being able to bridge medical and nursing care and are in an ideal position to direct changes in wound management care. Obviously, the most important wound management activity is the prevention of skin injury; however, that is not always possible. Some infants require procedures, such as surgery, that necessitate an incision. Other infants may experience extravasation of intravenous uids, 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

Stage 4: Remodeling The nal stage of wound healing is remodeling or maturation of the granulation tissue into mature connective tissue and/or scar. The wound also develops its nal strength during this stage of wound healing.25 The key cells for remodeling are macrophages and broblasts. ECM reshaping by cross-linking collagens, cell maturation, and program cell death or apoptosis are the mechanisms used in wound remodeling.10 Collagen synthesis peaks around 5 days after injury but continues for weeks or months.2 During this time, collagen and ECM tissue continue to be deposited into the wound, whereas the developing connective tissue is reshaped 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 activated by macrophages and broblasts, resulting in degradation of the matrix and differentiation of cells.28 Collagen is rst released in precursor form as a triple helix protein called

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Table 4. Strategies to Promote Wound Healing in Newborns/Infants Wound Healing Event Trageted Collagen maturation; wound contraction Metabolic activities within the wound microenvironment Collagen synthesis; broblast proliferation; keratinocyte mitosis Collagen synthesis and remodeling Keratinocyte migration; sequestering of growth factors

Care Strategy Maintain normal serum calcium levels Maintain normal perfusion

Scientic Rationale Actin-myosin contractility is calcium dependent39 Maximizes oxygen delivery to the wound bed

Maintain adequate oxygenation Maintain iron stores and/or provide ferrous iron Cover injuries with an occlusive hydrocolloid dressing

Collagen synthesis and secretion depends on oxygen-dependent enzyme reactions19 ; increases tissue resistance to infection2 Ferrous iron is a co-factor for collagen hydroxylation reactions19 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 uid that facilitates keratinocyte migration; the application of an occlusive hydrocolloid may decrease the risk of wound infection4043 Hypothermia decreases leukocyte mitotic activity44 ; the ideal wound temperature is 37 C44 Animal data shows that acute renal failure leads to inadequate granulation tissue production4547 ; chronic renal failure is associated with decreases in plasma bronectin concentration37 Infection prolongs the inammatory process, which delays wound healing; prolonged exposure to inammatory cytokines also produces tissue damage2 Corticosteroids have a substantial impact on every stage of wound healing; they reduce macrophage migration, suppress the inammatory response decrease keratinocyte and broblast proliferation, impair capillary budding, decrease ECM production, decrease protein synthesis, delay epithelialization, and block the release of vasoactive factors2,6,48,49 Additional protein is needed to meet the demands of wound healing49,50 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 Zinc is a co-factor for collagen synthesis,19 epithelialization, and broblast proliferation6 Copper is a co-factor for collagen cross-linking reactions6 Normal perfusion is needed to maintain the wound microenvironment and the developing ECM51 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

Keep the infant in a neutral thermal environment Maintain renal function

Prevent sepsis/infections

Avoid the use of corticosteroids

Inammatory cell activity; Leukocyte activity Production of granulation tissue; Fibroblast and keratinocyte proliferation Inammatory response; collagen synthesis; epithelialization Every aspect of wound healing

Maximize protein in parenteral and/or enteral nutrition Provide vitamins A, and C and B-complex vitamins (thiamine, niacin, riboavin, folate, B12 ) Provide zinc and copper

Collagen synthesis; wound contraction and remodeling Epithelialization; collagen synthesis; cell metabolism

Collagen synthesis

Maintain euvolemia Provide adequate pain management

Tissue oxygenation Wound perfusion; all aspects of wound healing

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facilitating wound healing and preventing complications of existing wounds. Physiologic-based care strategies to enhance wound healing are provided in Table 4. Two strategies that deserve special attention are the use of corticosteroids and wound dressings. Corticosteroids have a profound suppressive effect on the inammatory response and affect every aspect of wound healing. The use of corticosteroids 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 inammatory stage may decrease the negative consequences 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 tend to be based on prior experience and tradition rather than scientic 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 healing in the gauze or air-treated wounds. Other studies have shown that moisture-retentive, hydrocolloid dressings promote wound healing by increasing brinolysis and autolysis of necrotic tissue, facilitate the release of growth factors, reduce the time to heal, and promote 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 broblast 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 incubator or on a radiant warmer? Does humidication of the environment contribute to wound healing? Mulder et al37 discuss a number of studies evaluating the impact of jaundice on wound healing; their conclusion is jaundice clearly 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 the amino acids arginine and glutamine promote wound healing by improving collagen synthesis.38,39 Should newborns and infants with substantial wounds receive arginine and/or glutamine supplementation? Although these questions remain unanswered, it is clear that there are many areas for knowledge development in the understanding of wound healing in the infant population.

Conclusion

ound healing is a fascinating biologic event essential for human survival. Although many of the physiologic processes have been studied in animal and adult models, 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 invasive procedures. It is essential that clinicians understand the physiology of wound healing so they can provide competent care that optimizes the infants ability to heal and prevents further injury and/or complications.

References
1. Lazarus GS, Cooper DM, Knighton DR, et al: Denitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol 130:489493, 1994 2. Waldrop J, Doughty D: Wound-healing physiology, in Bryant, RA (ed): Acute and Chronic Wounds: Nursing Management (ed 2). St Louis, MO, Mosby, 1991, pp 1739 3. Schultz GS: Molecular regulation of wound healing, in Bryant, RA (ed): Acute and Chronic Wounds: Nursing Management (ed 2). St Louis, MO, Mosby, 1999, pp 413429 4. Haas AF: Wound healing. Dermatol Nurs 7:2834, 1995 5. Cooper DM: Wound healing: New understandings. Nurse Practitioner Forum 10:7486, 1999 6. Mast BA: The skin, in Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA, Saunders, 1999, pp 344355 7. Russell L: Understanding physiology of wound healing and how dressings help. Br J Nurs 9:1021, 1999 8. Adzick N, Longaker MT: Scarless fetal healing: Therapeutic implications. Ann Surg 215:1, 37, 1992 9. Martin P (1997): Wound healingAiming for perfect skin regeneration. Science 276:7581, 1997 10. Clark RAF: Wound repair: Overview and general considerations, in Clark RAF (ed): The Molecular and Cellular Biology of Wound Repair (ed 2). New York, NY, Plenum Press, 1995, pp 350 11. Steed D: The role of growth factors in wound healing. Surg Clin North Am 77:575586, 1997 12. Garrett B: Cellular communication and the action of growth factors during wound healing. Journal of Wound Care 6:277280, 1997 13. Hubner G, Brauchle M, Smola H, et al: Differentiation of regulation of pro-inammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokines 8:548556, 1996 14. Stallmeyer B, Kampfer H, Kolb N, et al: The function of nitric oxide in wound repair: Inhibition of inducible nitric oxide-synthase severely impairs wound reepithelialization. J Invest Dermatol 113:10901098, 1999 15. Weller R: Nitric oxide, skin growth and differentiation: More questions than answers? Clin Exp Dermatol 24:388391, 1999 16. Simpson DM, Ross R: The neutrophilic leukocyte in wound repair: A study with anti-neutrophil serum. J Clin Invest 51:20092023, 1972 17. Parks WC: Matrix metalloproteinases in repair. Wound Repair Regen 7:423432, 1999 18. Hunt TK, Hussain Z (1999): Wound microenvironment, in Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA, Saunders, 1999, pp 274281 19. Iocono JA, Ehrlich HP, Gottrup F, et al: The biology of healing, in Leaper DL, Harding KG (eds): Wounds: Biology and Management. Oxford, England, Oxford University Press, 1998, pp 1222

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20. Rohovsky S, DAmore P: Growth factors and angiogenesis in wound healing, in Ziegler T, Pierce G, Herndon D (eds): Growth Factors and Wound Healing: Basic Science and Clinical Applications. Norwell, MA, Springer, 1997, pp 234245 21. Kerstein MD: The scientic basis of healing. Adv Wound Care 10:3036, 1997 22. Garrett B: Re-epithelialisation. J Wound Care 7:358359, 1998 23. Garrett B: The proliferation and movement of cells during reepithelialisation. J Wound Care 6:174177, 1997 24. Eckes B, Aumailley M, Krieg T: Collagens and the reestablishment of dermal integrity, in Clark RAF (ed): The Molecular and Cellular Biology of Wound Repair (ed 2). New York, NY, Plenum Press, 1996, pp 493 512 25. Kerstein MD: The scientic basis of healing. Adv Wound Care 10:3036, 1997 26. Calvin M: Cutaneous wound repair. Wounds 10:1215, 1998 27. Levenson SM, Geever EF, Crowley LV: The healing of rat skin wounds. Ann Surg 161:293308, 1965 28. Streuli C: Extracellular matrix remodeling and cellular differentiation. Curr Opin Cell Biol 11:634640, 1999 29. Sandberg N: Time relationship between administration of cortisone and wound healing in rats. Acta Chir Scand 127:446455, 1964 30. Ehrlich HP, Hunt TK: Effects of cortisone and vitamin A on wound healing. Ann Surg 167:324328, 1968 31. Hunt TK, Ehrlich HP, Garcia JA, et al: Effects of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man. Ann Surg 170:633641, 1969 32. Eaglstein WH: The effect of occlusive dressings on collagen synthesis and re-epithelialization in supercial wounds, in Ryan TJ (ed): An Environment for Healing: The Role of Occlusion. International Congress and Symposium Series No 88. London, England, Royal Society of Medicine, 1985, pp 3138 33. Lydon MJ, Hutchinson JJ, Rippon M: Dissolution of wound congulum and promotion of granulation tissue under DuoDerm. Wounds 1:95 106, 1989 34. Madden MR, Nolan E, Finkelstein JL, et al: Comparison of an occlusive and a semi-occlusive dressing and the effect of the wound exudate upon keratinocyte proliferation. J Trauma 29:924931, 1989 35. Chen WY, Rogers AA, Lydon Mjl: Characteristics of biologic properties of wound uid collected during the early stages of wound healing. J Invest Dermatol 99:559564, 1992

36. Xia Z, Sato A, Hughes MA, et al: Stimulation of broblast growth in vitro by intermittent radiant warming. Wound Repair Regen 8:138144, 2000 37. Mulder GD, Brazinsky BA, Harding KG, et al: Factors inuencing wound healing, in Leaper DJ, Harding KG (eds): Wounds: Biology and Management. Oxford, England, Oxford University Press, 1998, pp 5270 38. Clark MA, Plank LD, Hill GL: Wound healing associated with severe surgical illness. World J Surg 24:648654, 2000 39. Kiehart DP: Wound healing: The power of the purse string. Current Biol 9:R602R605, 1999 40. Thomson P: The microbiology of wounds. J Wound Care 7:477 478, 1998 41. Hutchinson JJ: Prevalence of wound infection under occlusive dressings: A collective survey of reported research. Wounds 1:123133, 1989 42. Hutchinson JJ, McGuckin M: Occlusive dressings: A microbiologic and clinical review. Am J Infect Control 18:257268, 1990 43. Mertz PM, Marshall DA, Eaglstein WH: Occlusive dressings to prevent bacterial invasion and wound infection. J Am Acad Dermatol 12:662668, 1985 44. Lock PM: The effects of temperature on mitotic activity at the edge of experimental wounds, in Lundgren A, Soner AB (eds): Symposium on Wound Healing: Plastic Surgical and Dermatologic Aspects. Molndal, Sweden, 1980 45. McDermott FT, Galbraith AJ, Corlett RJ: Inhibitoin of cell proliferation in renal failure and its signicance to the uraemia syndrome: A review. Scott Med J 20:317327, 1975 46. Mott TJ, Ellis H: A method of producing experimental uraemia in the rabbit with some observations on the inuence of uraemia on peritoneal healing. Br J Urol 39:341345, 1967 47. McDermott FT, Nayman J, de Boer WG: The effect of acute renal failure upon wound healing: Histological and autoradiographic studies in the mouse. Ann Surg 168:142146, 1968 48. Robson MC: Disturbances of wound healing. Ann Emerg Med 17:12741278, 1988 49. Levenson SM, Demetriou AA: Metabolic factors, in Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA, Saunders, 1999, pp 248273 50. Flanigan KH: Nutritional aspects of wound healing. Adv Wound Care 10:4852, 1997 51. Partridge C: Inuential factors in surgical wound healing. J Wound Care 7:350353, 1998