Wounds, whether created electively or as a result of traumatic injury, are an integral component of the surgical patient thus understanding the pathways and mechanisms of wound healing is critical for the optimal care of surgical patients. This fund of knowledge is applicable to the care of patients with acute wounds as well as facilitates the development of therapeutic options for patients with chronic or nonhealing wounds. Wound healing is often divided into phases in order to aid understanding of this complex process and these are the early inflammatory phase, the intermediate proliferative phase, and the late maturational and remodeling phase. Although these phases are often described as discrete events, it is important to realize that characteristics and elements of these phases overlap. Wound repair is a dynamic and complex process of inflammation characterized by a well-coordinated pattern of cell migration, proliferation and differentiation, along with angiogenesis and matrix remodeling. The essential characteristics of the early phase include hemostasis and inflammation. The intermediate phase is characterized by cell proliferation, migration, angiogenesis, and epithelialization while the late phase involves collagen production with contraction of the wound. Ultimately, even in normal wounds, the wound undergoes continuous remodeling for the rest of the patient’s life (Table 47-1).

Wounds can heal by either regeneration or by repair but the vast majority of wounds in humans heal by repair. “Regeneration,” a process that involves replacement of damaged tissue with an exact replica which is indistinguishable from the original both morphologically as well as functionally, does not occur in mammalian skin. Rather, a process of “repair” occurs wherein a physiologic adaption of the injured tissue occurs to reestablish coverage or continuity that does not attempt to offer an exact replacement of the damaged skin. Thus, all mammalian wounds heal by scarring or repair and not by regeneration.

The process of wound healing starts with the inflammatory phase which commences as soon as the wound is created. Critical to this early phase, the wound must undergo hemostasis of disrupted blood vessels, clearing of any bacterial invaders and removal of devitalized tissue. Injury to tissue initiates a wide array of responses that alter the cellular and molecular milieu of the wound which formulates the basis for a coordinated pathway to resolve the tissue injury. Cessation of blood loss is initially driven by vasoconstriction as vascular smooth muscle contracts as does the endothelium under the influence of endothelin, a potent endothelium-derived vasoconstrictor.¹ Other early mediators of vasoconstrictors include catecholamines, prostaglandins from injured cells, bradykinin and thromboxane A2. Later vasoconstriction is driven by platelet activation with the release of factors from these platelets including serotonin and additional bradykinin and thromboxane A2.

Hemostasis is ultimately achieved via activation of platelets and humoral factors called coagulation or clotting factors. These factors are activated sequentially in a cascade comprised of two pathways, the intrinsic and extrinsic pathways, with the extrinsic pathway being the most critical to hemostasis following tissue injury. Exposed tissue factor on the subendothelial surface contributes to activation of the extrinsic coagulation pathway by binding circulating factor VII which leads to activation of factors IX and X and thrombin production. Thrombin then acts as a catalyst converting fibrinogen to fibrin which makes an interwoven clot as well as initiates additional platelet activation.²

The initial tissue trauma disrupts the endothelium and exposes subendothelial collagen, particularly type IV and V collagen, which leads to platelets aggregation and activation. Normally, platelet activation by the vessel wall is inhibited by negatively charged glycosaminoglycans on the endothelium that prevent adherence of platelets, but in their absence collagen is exposed, platelets are activated and tight adherence of platelets to the vessel wall occurs. Platelet adherence is also critically dependent upon von Willebrand factor (vWF) and is a result of a complex of the platelet glycoproteins VI, Ib-V-IX, the exposed collagen bound vWF and platelet integrins, the most important of these being the αIIbβ3 integrin.³ The combination of collagen and platelets in the presence of thrombin and fibronectin leads to cytokine and growth factor release from platelet α-granules. These include platelet derived growth factor (PDGF), transforming growth factor-β (TGF-β), platelet activating factor (PAF), serotonin and fibronectin. These activated platelets along with the fibrin clot acts as scaffolding for influxing cells such as neutrophils, fibroblasts, and monocytes.

Platelets

As already discussed, platelets are integral to clotting and release an array of factors which aid in additional platelet adhesion, hemostasis, clot formation and clot remodeling. Platelets serve as an adhesion site for coagulation factors and at the same time serve as an important source of coagulation factors, including factors V and XIII. Soluble agonists, such as adenosine diphosphate (ADP) released from dense granules, accumulate in the rapidly developing clot and contribute to a positive feedback cascade which further enhances and sustains platelet activation as well as recruits large numbers of circulating platelets. One of the most important platelet interactions occurring early in the wounded tissue, and is a major driver of the early hemostatic phase of wound healing, is the ADP/P2Y12 interaction. P2Y12 is a G-protein-coupled receptor found mainly on the surface of platelets and is known to couple with secreted ADP to strengthen and enhance platelet adherence and aggregation. Antiplatelet agents, such as clopidogrel, act by disturbing this ADP/P2Y12 interaction and thus inhibiting thrombus formation. This action, which is desirable in patients at increased risk for thrombotic events, may have devastating consequences following a traumatic event.⁴ Variations in the density of the thrombus plug generated by the ADP/P2Y12 interaction appear to be dependent on the shear forces experienced by the platelet at varying sites which modulates clotting and assists in its regulation.

Activated platelets release over 300 active substances from three predominant types of platelet storage compartments, namely the dense granules, α-granules and lysosomes, and contribute to clot formation as well as vasodilation and increased vascular permeability which allows diapedesis, important for the next phase of wound healing.⁵ Dense granules contains the small molecules adenosine triphosphate (ATP) and calcium which activate other platelets and the vasoactive substance, serotonin. α-Granules contain polypeptides, insulin-like growth factor (IGF-1), platelet-derived growth factor (PDGF) and many cytokines which lead to platelet adhesion and aggregation via P-selectin and von Willebrand factor. Lysosomes release enzymes such as cathepsin-D that mediate clot remodeling. Although the exact mechanisms of granule formation and release remain unknown, fusion of these storage compartments with the platelet plasma membrane is essential to allow release of these factors, recently it has been revealed that a key mediator of granule release involves the Soluble NSF Attachment Protein Receptor (SNARE) proteins and a set of SNARE chaperones.⁶ Defects in the SNARE mechanism lead to a significant lack of thrombus formation⁷ and it is likely that advances in our understanding of SNARE mediated granule release will lead to better understanding of platelet function, important for both wound healing and thrombotic disease.

Platelets express integrin receptors that mediate both direct and indirect ligation to subendothelial ligands.^8,9 The glycoprotein Ib-IX-V (GPIb-IX-V) complex, consisting of four subunits namely GPIbα, GPIbβ, GPIX, and GPV, mediates a critical step in platelet adhesion binding to von Willebrand factor (vWF) on damaged endothelium and involves other ligands such as thrombin, and P-selectin. P-selectin glycoprotein ligand-1 (PSGL-1) found on leukocytes and endothelium, interacts with P-selectin present on both activated vascular endothelial cells and activated platelets resulting in tight platelet adherence. In part, it is this tight interaction between platelet α-granule derived P-selectin and PSGL-1 that facilitates transendothelial migration of neutrophils during inflammation.¹⁰ Once activated, platelets serve as a platform upon which an insoluble fibrin meshwork is built and serves to trap both additional platelets as well as erythrocytes contributing to a dense fibrin plug.

The complement cascade, a highly conserved series of plasma proteins, is initiated shortly after wounding and results in the release of potent neutrophil chemotactic factors such as C5a. The overly robust activation of the complement cascade seen with large wounds is in part a mediator of the systemic inflammatory response syndrome (SIRS) seen following traumatic injury. C5a also plays a sentinel role in the apoptotic response within immune cells following tissue wounding. Complement aids in bacterial clearance from the wound through the formation of the membrane attack complex, as well as tagging or opsonizing bacteria to facilitate their phagocytosis.

Polymorphonuclear Cells

Following the formation of the platelet plug, neutrophils are the next cell type to appear in significant number is the wound, arriving as early as 6 hours following wounding and predominating for the next 24–48 hours. The initial neutrophil influx is stimulated by a cloud of early inflammatory mediators, including prostaglandins, bacterial products, tumor necrosis factor alpha (TNF-α), transforming growth factor-beta (TGF-β) and interleukin-1 (IL-1). Components of the complement cascade in the wound promote neutrophil influx and adherence, especially when coupled with thrombin and platelet-aggregating factor. The source of these neutrophil chemoattractants is diverse but also includes the injured keratinocytes, which show early production of chemokines following injury in addition to their critical function of reepithelialization in the late phase of wound healing.

The inflamed wound environment is associated with increased capillary permeability that facilitates neutrophil diapedesis. These recruited neutrophils release further cytokines, growth factors and chemokines, including TNF-α, IL-1β, and IL-6 adding to the inflammatory milieu of the wound. Lysosomal contents, reactive oxygen species and enzymes such as elastase released into the extracellular matrix (ECM) increase vascular permeability and promote further neutrophil influx. Neutrophil migration through the ECM is controlled through integrin interactions. The selectin family of integrins includes those expressed by leukocytes (L-selectin), vascular endothelium (E- and P-selectins), and platelets (P-selectin). Firm adhesion is mediated by intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and their integrin ligands, including lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) and very late antigen-4 (VLA-4, CD49d/CD29). The phases of integrin mediated neutrophil migration are: adhesion, spreading, contractility, and retraction. Notable integrins responsible for neutrophil adhesion and migration at this stage are integrin β1 and β2. Binding sites for integrin interaction in the ECM have been identified on fibronectin, laminin, and collagen, all of which are found in the wound environment.

Upon entry into the wound environment, neutrophil functional activity is increased by cytokines which manifests as increased cytotoxicity and cytokine release. Neutrophils elaborate vascular endothelial growth factor (VEGF) and IL-8 as part of the coordinated vascular response to tissue injury. Polymorphonuclear cell (PMN)-released IL-6 contributes to the early activation of epidermal cells and prepares them for migration. Bacterial phagocytosis, aided by complement mediated bacterial opsonization, protease driven tissue debridement and scavenging of necrotic debris are the main functions of PMNs during this early phase.¹¹ Neutrophils also generate oxygen free radicals and superoxide anion which are toxic to bacteria in the wound and also serve as signaling molecules for other cells.

Wound contamination is typically controlled within 24–48 hours and PMN influx and migration stops. This neutrophil activation and influx into the early wound is critical to subsequent wound macrophage development and cytokine production. Several factors are noted to lead to a persistence of PMNs in the wound, including ongoing wound contamination, early wound infection or an excessive stress response.¹² The constant presence of chemotactic factors and ongoing activation of the complement systems resulting in a continuous influx of PMNs into the wound with delays in wound healing and prolongs wound necrosis and inflammation and leads to aberrant wound healing.

Macrophages

Following the critical functions of PMNs, macrophages appear in the wound at approximately 48 hours, their numbers peaking around day 3 and persisting within the wound until completion of wound healing.^13,14 Macrophages are absolutely vital to wound healing and their functions include debridement, promoting angiogenesis, matrix synthesis and elaboration of countless cytokines, growth factors and chemokines. Macrophage chemoattractant protein-1 (MCP-1) serves as a strong stimulant for monocyte influx and promotes both macrophage and T-cell migration into the wound. Similarly to neutrophils, integrins are important for monocyte chemotaxis and entry into the wound environment. Integrin activation also promotes monocyte phenotypic changes to transform from monocytes into wound macrophages as well as stimulates macrophage phagocytic activity.¹⁵

Early activation of wound macrophages is, in large part, driven by platelet derived mediators. Once activated, macrophages are noted to release nitric oxide and a variety of cytokines which modulate fibroplasia and angiogenesis and cytokines such as IL-1 which mediates the febrile response to injury, enhances collagenase production and promotes cellular chemotaxis. IL-6 from monocytes and macrophages stimulates stem cell growth, lymphocyte activation, and fibroblast proliferation and modulates acute phase reactants. TNF-α is released in response to microbes in the wound, however this critical mediator of the inflammatory response may be elaborated in sterile wounds as well. It also mediates the interaction between immune cells and the endothelium but a persistent and exaggerated TNF-α response has been associated with chronic and nonhealing wounds, and may be a contributor to organ failure. IL-8 mediates cellular migration, degranulation, cellular adhesions, and keratinocyte maturation while Interferon-γ (IFN-γ) aids in tissue remodeling and collagen metabolism. TGF-α has been shown to stimulate angiogenesis and epidermal growth while TGF-β, which has at least three isoforms, is a very potent stimulant of fibroplasia and ECM remodeling. TGF-β1 affects collagen metabolism and is critical to bowel anastomotic healing. Rising TGF-β concentrations in the wound stimulate fibroblasts to make collagen and fibronectin thus prompting the proliferative phase of wound healing. Proteases, including metal metalloproteinases (MMPs), are also released from the wound macrophages which degrade the ECM allowing cell migration and facilitate removal of foreign materials. A significant effect of these macrophage derived cytokines is to phenotypically, and thereby functionally, alter wound fibroblasts.^16,17 Notable macrophage mediated alterations in wound fibroblasts include increased collagen synthesis and an increase in matrix contraction but uncontrolled acute and chronic stress induces disorganized wound inflammation^18,19,20,21 and thus may lead to poorly healed wounds. Excess epinephrine, present in exaggerated inflammatory responses, alters the neutrophil influx into wounds, as well as activation of macrophages by binding of the β₂-adrenergic receptor (β₂AR) in a dose dependent manner negatively modifying the inflammatory response to injury.

Intermediate Proliferative Phase

Whilst the early phases of wound healing involve debridement of bacteria and dead tissue and migration of inflammatory cells into the wound, the proliferative phase is characterized by a brisk synthesis of ECM, collagen, and other cells critical to wound repair. The proliferative phase occurs from about day 4 to day 12 and may be broken into three major components, namely angiogenesis, fibroplasia, and epithelialization.

Angiogenesis

Angiogenesis involves formation of new vasculature within the wound and is important to sustain the cells rebuilding and healing of the wound. The early phases of angiogenesis occurs as early as day 2 following wounding as healthy tissue adjacent to the wound sprouts capillary buds which then extend into the wound. Following tissue wounding and vascular injury, the endothelium of damaged vessels is degraded by matrix degrading enzymes such as MMPs and plasmin while the basement membrane of the postcapillary venules undergo degradation by activated endothelial cells. MMP-2 and MMP-9, driven by wound hypoxia, have been shown to be crucial to basement membrane breakdown, an important step that facilitates endothelial cell migration into the wound. Once again, adhesion molecules such as integrins, coupled with adherence of fibrinogen and fibronectin, allows endothelial cell migration along the matrix scaffold in the healing wound. These endothelial cells undergo division resulting in tubule and lumen formation such that the newly formed capillary buds eventually branch and loop and encircle forming a plexus of capillaries, clinically defined as granulation tissue. The formation of capillary tubules, with cell to cell and matrix interactions, is modulated by endothelial surface molecules, including platelet endothelial cell adhesion molecule (PECAM-1) for cell–cell interactions and β1-integrin receptors for contact stabilization and tight junction formation. Endothelial cell adherence is promoted through upregulation of cell surface adhesion molecules such as VCAM-1. The newly formed capillaries diverge along one of two pathways, either differentiation into arterioles or succumbing to apoptosis and ingestion by macrophages.

Cytokines and chemokines, predominantly produced by macrophages and platelets, as well as local factors such as wound tissue acidemia and hypoxia contribute to endothelial growth and angiogenesis. Heparan, a glycosaminoglycan, stimulates capillary endothelial cell migration while disrupted parenchymal cells release both acidic and basic fibroblast growth factor (b-FGF) jumpstarting angiogenesis within three days of wounding. VEGF, produced in large amounts by keratinocytes, fibroblasts, and macrophages in response to tissue damage and hypoxia, is a strong angiogenic stimulant during days 4–7. Endothelial cell proliferation is enhanced by both EGF and TGF-α while the inflammatory cytokine TNF-α, as well low oxygen tension in the wound, are known to mediate angiogenesis via induction of hypoxia-inducible factor-1 (HIF-1).²² HIF-1 is another early mediator and is found in the wound as early as 24 hours after wounding and lasts for up to 5 days. TGF-β assists angiogenesis though production of FGF by fibroblasts. Several of the components of the healing wound such as fibronectin, produced by wound macrophages, as well as hyaluronic acid and collagen also play important roles in wound angiogenesis highlighting yet another critical function of the macrophage in wound healing. Lactic acid, produced through anaerobic metabolism in the wound, is a potent stimulant for the release of endothelial growth factors from the wound macrophages. As angiogenesis progresses and oxygen delivery to the wound improves, the hypoxic stimulus to macrophages abates and factors such as factor inhibiting HIF-1 (FIH-1) lead to down regulation of HIF-1.

Fibroplasia

Fibroplasia involves fibroblast proliferation and matrix synthesis. Fibroblasts, derived from resting mesenchymal cells, appear by day 3 after wounding and peak at day 7. Under noninjured conditions, fibroblasts have little, if any actin-associated cellular or matrix fixation but following tissue wounding, fibroblasts are stimulated to migrate toward the wound and to synthesize extracellular matrix materials. Fibroblasts enter the wound in response to signals from platelet derived products such as insulin-like growth factor (IGF-1), EGF, platelet-derived growth factor (PDGF) and TGF-β. These platelet and macrophage derived growth factors induce chemotaxis and subsequent activation and proliferation of these normally quiescent cells. Fibroblasts, endothelial cells, and smooth muscle cells enter the wound and begin matrix deposition, angiogenesis, and epithelialization that ultimately lead to coverage of the wound. Further fibroblast migration occurs in response to growth factors and cytokines from wound macrophages and fibroblasts themselves.

Fibroblasts are responsible for producing the vast majority of structural proteins needed for tissue repair, the most important of which is collagen. Collagen appears concomitant with the appearance and activity of wound fibroblasts, and is first detectable in the wound at day 3, rapidly increasing thereafter for up to the next 3 months. Approximately 4 weeks after wounding, the rate of collagen synthesis declines matching the rate of MMP-1 (collagenase) activity and collagen breakdown and collagen remodeling and modification ensues. Although initially deposited in the wound in a haphazard fashion, the collagen fibrils are organized by cross linking into coordinated and aligned bundles which mimic the stress and tension lines of the wound and the surrounding native skin.

Epithelialization

While the deeper, strength layers are being laid down the superficial epithelial integrity is being reestablished at the wound surface in a process known as epithelialization, or coverage of the denuded epithelial surface by intact epithelium. Although the mechanisms that induce reepithelialization remain unclear, the process is in part mediated by loss of contact inhibition, fibronectin production and driven by a variety of macrophage and lymphocyte derived cytokines. It has been shown that epidermal growth factors (EGF), fibroblast growth factor family (FGF) members, insulin like growth factor, several cytokines and TGF-β stimulate epithelial cell mitogenesis and chemotaxis which is central to reepithelialization. Upregulation of matrix metalloproteases (MMPs) alters and remodels the extracellular matrix to favor epithelial cell migration as well.^23,24

The process of reepithelialization begins early, within the first several hours following wounding, as epithelial cells from either the wound margins or from dermal epithelial appendages become activated. Activated keratinocytes adjacent to the wound produce multiple signaling molecules that act in both autocrine and paracrine fashions on multiple wound bed cells. For example, keratinocytes release prestored IL-1 and TNF-α that further aids keratinocyte proliferation and migration as well as acts on nearby fibroblasts to produce keratinocyte growth factor (KGF) a strong promoter of keratinocyte proliferation and migration. TGF-β expression is upregulated early following wounding, elaborated by both keratinocytes and fibroblasts, and induces granulation tissue formation, encourages myofibroblast differentiation leading to collagen matrix contraction and wound closure. TGF-β also plays an important role in phenotypic alterations of the activated keratinocytes but in nonhealing wounds it appears to be suppressed leading to nonmigratory keratinocytes and wound stasis.

Basal keratinocytes are normally attached to the basement membrane through desmosomes, hemidesmosomes, and focal adhesions points.²⁴ Cells at the wound edge are noted to lose these tight attachments, which is a prerequisite for keratinocyte migration and integral to reepithelialization. The transcriptional factor Slug has been shown to be critical to desmosomal disruption and thus keratinocyte release,²⁵ allowing them to begin their migration across the wound. This is coupled with alterations in integrin expression, facilitates migration rather than adhesion. The migration of these edge basal cells during wound closure has been described as being akin to cells “leap frogging” over one another rather than crawling across the wound.^26,27 As the migrating epithelial cells advance and begin to cover the wound, proliferation begins to ensure that sufficient cells are available to cover the wound. Keratinocytes in chronic and nonhealing wound edges are different in that their receptiveness to both migratory and proliferative stimuli is blunted. Furthermore, these functional alterations may, in part explain why topically applied EGF has failed to show improved healing when it has been applied to chronic wounds in clinical trials.²⁸ FGF2 produced by fibroblasts stimulates epithelialization via paracrine effects and acts on the KGFR2IIIb receptor found exclusively on keratinocytes to promote proliferation and migration.²⁹ While EGF promotes and stimulates keratinocyte migration, it has been shown that glucocorticoids impede EGF mediated cellular migration likely through significant alterations in the cytoplasmic location of the EGF-receptor in keratinocytes and is one of the mechanism whereby steroids impede wound healing.

Migration through the newly synthesized ECM is facilitated by a strict balance of MMPs and tissue inhibitors of metalloproteinases (TIMPs). MMP-1 is expressed in large amounts at the wound edges and promotes keratinocyte migration on type I collagen, but this action is balanced by TIMPs. Chronic nonhealing wounds are characterized by dysregulated MMP/TIMP ratios and function. Keratinocytes also play a role in controlling the wound environment and respond to the presence of bacterial products in the wound through Toll-like receptor (TLR) signaling³⁰ as well as the production and release of antimicrobial peptides (AMPs).³¹ AMP levels rise quickly after wounding and decline with wound closure. Dysregulation and altered expression of both TLRs and AMPs are hallmarks of chronic nonhealing wounds. Once the wound has been bridged, the migrating epithelial cells change shape to become more columnar with the surface keratinized shortly thereafter. For a wound in which the edges have been reapproximated, the process is complete in about 48 hours but this time may be dramatically longer in larger, more complex wounds.

Whereas normal skin only displays mitotically active keratinocytes in the basal layer, chronic wounds are characterized by cellular division throughout the suprabasal layers. This hyperproliferative activity is partly resulting from c-myc activation and overexpression and a deregulation of keratinocyte differentiation and activation pathways.^32,33 When TGF-β signaling is suppressed in the wound, chronic wounds may ensue in part from the nonmigratory nature of the wound keratinocytes and alteration in the balance of MMPs and their inhibitors as well as derangements in the composition of various keratinocyte growth factors.

Late Maturational and Remodeling Phase

Collagen Metabolism

Collagen formation and deposition is critical to the reconstructive phase of wound healing and the transition to the remodeling phase of wound healing is delineated by a state of collagen equilibrium. Wound collagen content reaches maximal levels in the wound by 2–3 weeks and the point of equilibrium is noted when the rate of collagen synthesis is matched by the rate of collagen degradation. Many types of collagen have been identified, but they all share a similar structure of a right-handed triple helix. In general, collagen triple helices are comprised of three alpha peptide chains which undergo extensive modifications but collagen synthesis is highly regulated at all stages. The initial polypeptide chain translated from mRNA is called protocollagen. Release of protocollagen into the endoplasmic reticulum results in hydroxylation of proline into hydroxyproline and lysine into hydroxylysine, thus collagen comprises large amounts of these unique amino acids. Critical cofactors in this step include iron and oxygen, coupled with ascorbic acid functioning as an electron donor. Wound hypoxia, with lactic acid buildup, adversely effects collagen production at this critical juncture which may be a mechanism of poor wound healing in diabetes and peripheral vascular disease. Protocollagen undergoes glycosylation by linking glucose and galactose at hydroxylysine residues and these changes transform the protocollagen chain into an α-helix configuration. Three of these α-helical chains then entwine into a super-helical structure called procollagen. Covalent crosslinking of the lysine residues renders the procollagen molecule much stronger than nonlinked molecules. Following post-translational modifications, the triple helix is secreted as procollagen into the extracellular environment where the propeptide ends are cleaved by both procollagen-C-proteinases and procollagen-N-proteinases. The free amino acid groups of some lysine and hydroxylysine are changed into aldehyde residues which are then cross-link with the nontransformed lysine or hydroxylysine residues leading to fibril formation.

This process of ongoing wound healing may last up to 1 year, and remodeling may continue indefinitely, but the strength of the wound never reaches that of un-injured tissue. Assessing breaking strength of wounds reveals that after 1 week the wound has only approximately 3% of the breaking strength of normal tissue, which increases to 20% by 3 weeks. As long as healing occurs without incident, the scar strength reaches approximately 80% of normal tissue strength by 3 months.^34,35,36

Matrix Deposition

The remodeling that defines the later phase of wound healing starts approximately 21 days post-injury and may last up to 1 year before proceeding at a near static pace. Apoptosis stops granulation tissue capillary development and the mature wound is both avascular and in large part acellular.³⁷ The decline in angiogenesis with decreased blood flow to the wound coincides with the reduction in the metabolic activity of the wound. This phase of wound healing is marked by changes in both the matrix composition as well as collagen which enhance the strength of the maturing wound. The fibrin and fibronectin of the early, cell recruitment, phases of the wound are replaced by proteoglycans and glycosaminoglycans which promote matrix remodeling allowing collagen to be the predominant protein in the healing scar.

A change in type of collagen in the healing wound is now noted. Normal tissue normally contains only about 10% type III collagen with type I accounting for the other 80–90%; however, fibroblasts actively produce type III collagen during the early phases of wound healing yielding about 30% of the collagen found in the wound. During the remodeling phase of wound healing, this abundance of type III is replaced by type I collagen to restore normal collagen ratios. The type 1 collagen of the remodeling phase lies in small parallel bundles, a marked difference from the basket-weave of normal dermis. The collagen of the healing wound differs from normal collagen in that it is thinner and displays more hydroxylation and glycosylation. The thinner collagen fibers of the healing wound gradually thicken, organizing along stress lines and this is associated with an increase in scar wound tensile strength and it is noted that wound strength correlates with fiber thickness.³⁸ Despite thickening and strengthening, scar breaking strength is never as strong as the strength of normal unwounded tissue.

Remodeling and Myofibroblasts

Wound remodeling is characterized by wound contraction from the edges of the wound to the center in a centripetal fashion due to a complex interplay between fibroblasts and the extracellular matrix material. During reepithelialization the wound edges progress toward each other at a rate of 0.6–0.75 mm/d and this rate of contraction is dependent upon a wide variety of factors. Fibroblasts in the healing wound undergo transformation into myofibrolasts, which has been known for nearly 50 years when they were recognized as modified fibroblasts with smooth muscle features, and their main function is wound contraction through ECM organization. As the wound environment and ECM changes with alterations in stress forces across the wound, fibroblasts are stimulated and acquire contractile properties and “stress fibers,”³⁹ which are cytoplasmic alpha smooth muscle actin arranged in bundles. Stress fibers connect to the fibrous ECM proteins via integrin mediated cell-matrix junctions. The expression of de novo α-smooth muscle actin (α-SMA) denotes a differentiated wound myofibroblast with an increased contractile activity.⁴⁰ As noted, myofibroblasts attach to collagen with the aim of wound contracture, largely through the action of actin.⁴¹ This process requires TGF-β, specialized variants of ECM proteins including variants of fibronectin, and the high mechanical stress seen in the healing and remodeling ECM.³⁹ During wound contraction, MMP-3 activity is also critical to detach excessive connections between myofibroblasts and collagen to allow migration and contraction. Following tissue repair the ECM takes on the stress load and the mechanical work of the wounded area, thus releasing the myofibroblasts from the stress load at which point they undergo apoptosis and disappear from the wound. A persistence of fibroblasts and myofibroblasts is found in disease states marked by chronic fibrosis. Full thickness wounds are noted to heal with scarring due to abnormal arrangement of the collagen fibers as well as aberrant contractile forces in the wound environment and the degree of scarring appears to be related to the degree of inflammation that occurs during wound healing.¹¹

The management of wounds is best considered by dividing wounds into two categories: acute and chronic wounds. All wounds should be considered at risk for tetanus infection and the patient should receive tetanus prophylaxis. Tetanus prophylaxis is reviewed in Table 47-2 while Table 47-3 reviews the characteristics of a wound that is tetanus prone. The majority of acute surgically created, and a substantial portion of acute traumatic wounds, can be closed by prompt approximation of the wound edges and healing by primary intention. Essential features of the closure and management of the wound are to ensure gentle tissue handling to avoid crushing the tissues, approximating the wound without undue tension and to apply a sterile occlusive dressing that should stay in place for approximately 48 hours. Although there are a multitude of potential dressings that can be applied, none has been demonstrated to be clearly superior to any other. Closure of the wound by tertiary intention involves a delayed primary closure of the wound and it is often used in cases where the wound is initially too contaminated for primary closure. Cleansing of these wounds occurs through both cellular (phagocytosis) and physical (repeat debridement and frequent dressings) means to the point wherein by day 3 or 4 the wound edges can be safely reapproximated primarily.

It is estimated that up to 6 million individuals have chronic or poorly healing wounds in the United States thus it is important to focus on caring for these wounds. Although several definitions exist, a chronic wound is generally defined as a wound that has failed to heal after 3 months and is associated with increased cost and prolonged morbidity. Examples of poor wound healing may be seen in complications of elective cases, infected wounds from trauma, pressure ulcerations and diabetic or venous ulcer wounds. Wound healing may be complicated by a number of factors including the size, depth and extent of the wound as well as patient related factors such as obesity, malnutrition and medical comorbidities (Table 47-4). In such cases, the wound cannot be closed and must heal by secondary intention. Further, since wound healing is critically dependent upon an intact immune and inflammatory system, immunocompromised patients will often display marked impairments in wound healing as seen in diabetes, advanced malignancy, or in those on steroids or immune suppression following organ transplantation. In many cases a clinician can identify a wound at increased risk for chronicity shortly after wounding based on the aforementioned combination of wound and patient factors so that care can be focused on maximizing the elements essential to healing.

Dressings for chronic wounds are used to achieve three main objectives: cover the wound and protect it from contamination, absorb any bodily fluids preventing maceration which may promote bacterial growth, and protection against desiccation and mechanical injury. Additionally, the ideal dressing should be easy to apply, cost effective, and relatively unobtrusive. A long trusted standard for wound management remains the application of gauze dampened with saline solution that is changed frequently. Healing by this manner is often slow, and a significant portion of wounds will never progress to full wound healing. Furthermore the need for frequent dressing changes may limit the daily activities of the patient and the debriding action of this type of dressing is often painful. The number of specialized dressings and wound management adjuncts has occurred but no therapy has revolutionized wound care to the degree that subatmospheric pressure dressings have.

Negative pressure wound therapy (NPWT) also known as vacuum-assisted closure (VAC) or micro-deformational wound therapy (MDWT) utilizes a dressing that applies continuous or intermittent negative pressure to the wound. Over the years, the material used, pressure applied and indications for, and goals of NPWT have changed and expanded. NPWT has even extended into the management of complex traumatic wounds, where it was previously thought that there is little role for them. The initial goal of NPWT in patients with traumatic soft tissue wounds is to provide coverage following wound debridement in wounds unable to be definitively closed at the initial setting. The reasons precluding initial definitive closure include patient related features such as hemodynamic stability as well as wound features such as degree of contamination, need for further debridement or in cases where the viability of tissue in the wound is uncertain but debridement of that tissue is not advisable. In these settings NPWT can aid in preventing wound desiccation, facilitate wound drainage and contribute to decreasing the wound bacterial burden; however, it must be stressed that NPWT is not an alternative to appropriate surgical debridement when clinically indicated. The presence of necrotic material in the wound remains a contradiction to the placement of NPWT as does the presence of an uncontrolled enteric fistula, active bleeding, untreated osteomyelitis or malignant wounds. However, when used for appropriate indications, NPWT has been shown to improve a wide range of outcomes including decreased hospital length of stay and cost of wound care, improved time to wound closure and decreased overall complication rates.⁴²