Plastic surgery

PART I

PRINCIPLES, TECHNIQUES, AND BASIC SCIENCE

CHAPTER 2  WOUND HEALING: NORMAL AND ABNORMAL

GEOFFREY C. GURTNER AND VICTOR W. WONG

THE RESPONSE TO INJURY

What is wound healing? Definitions might include the repair or reconstitution of a defect in an organ or tissue, commonly the skin. However, it is clear that the process of wounding activates systemic processes that alter the physiology far beyond the confines of the defect itself. Inflammatory cascades that impact nearly every organ system and have potentially dire consequences for survival are initiated, as illustrated by multisystem organ failure. Furthermore, recent research implicating the participation of stem and progenitor cells in the wound healing process requires a broader perspective than one that focuses solely on the defect itself.1,2 Wound healing may be best understood as an organism’s global response to injury, regardless of whether the location is in the skin, liver, or heart. Seen from this perspective, it is certainly not an exaggeration to regard the response to injury as one of the most complex physiologic processes occurring during adult life.

The complexity of this process is easily demonstrated in cutaneous wound healing. During the progression from a traumatic injury to a stable scar, the intrinsic and extrinsic clotting system are activated; acute and chronic inflammatory responses occur; neovascularization proceeds through angiogenesis and vasculogenesis; cells proliferate, divide, and undergo apoptosis; and extracellular matrix (ECM) is deposited and remodeled. These (as well as other events) occur simultaneously and also interact and influence each other at the level of gene transcription and protein translation in a dynamic and continuous fashion. Further, normally sterile tissues encounter and interact with bacteria and other elements of the external environment in a way that never occurs except following injury. Thus, it is not surprising that wound healing and the response to injury are still poorly understood by scientists and clinicians alike, except at a purely descriptive or empiric level. The sheer number of commercially available products of unproven efficacy is a testament to the lack of mechanistic understanding regarding this most common surgical problem.

Most textbook chapters on wound healing are an encyclopedic catalog of the phenomenology of wound healing. They list the multitude of cytokines and growth factors that are observed during wound healing, usually based on experimental models or in vitro systems that may be prone to artifact. With the increasing sensitivity of new technologies such as quantitative polymerase chain reaction and microarray, the list of cytokines, growth factors, chemokines, etc. that appear during wound healing continues to grow at an alarming rate. How will we ever make sense of this mountain of data so that we can intervene and alter the outcome of wound healing/response to injury? In this chapter, a theoretical framework with which to classify wound healing will be proposed. The broad biologic transitions that occur during cutaneous wound healing (i.e., inflammatory phase, proliferative phase, and remodeling phase) will be described within this context. An abbreviated list of major “factors” will be provided but not discussed in detail since it remains unclear which of these factors are of primary or incidental importance in either functional or abnormal wound healing. Finally, an attempt will be made to understand abnormal human healing within the proposed theoretical context. For a more detailed list of the myriad events occurring in wound healing, the reader is referred to a number of excellent recent reviews.3-5 However, given the inherent lag in book publication and the rapid pace of the field, the reader should refer to Medline (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and search for the latest reviews in the field of wound healing to obtain the most up-to-the-minute information.

SCAR FORMATION VERSUS TISSUE REGENERATION

As discussed, wound healing is an extremely broad and complex topic covering a variety of responses to injury in a variety of different organ systems. However, some common features exist. Generally, wound healing represents the response of an organism to a physical disruption of a tissue/organ to re-establish homeostasis of that tissue/organ and stabilize the entire organism’s physiology. There are essentially two processes by which this re-establishment of homeostasis occurs. The first is the substitution of a different cellular matrix as a patch to immediately re-establish both a physical and physiologic continuity to the injured organ. This is the process of scar formation. The second process is a recapitulation of the developmental processes that initially created the injured organ. By reactivating developmental pathways, the architecture of the original organ is re-created. This is the process of regeneration.6

The dynamic balance between scarring and tissue regeneration is unique to different tissues and organs (Figure 2.1). For example, neural injury is characterized by little regeneration and much scarring, whereas hepatic and bone injury usually heals primarily through regeneration. It is important to note, however, that the liver can respond to injury with scarring as it does in response to repetitive insults during the progression of alcoholic cirrhosis. Moreover, the same injury in phylogenetically related species can result in very different responses. Thus, limb amputation in newts results in limb regeneration, whereas in humans, only scarring can occur.

It is important to realize that the balance between scar and regeneration is likely subject to evolutionary pressures and may, in fact, be functional. Thus, a cutaneous injury in our prehistoric predecessors disrupted their homeostasis with respect to thermoregulation, blood loss, and, most importantly, prevention of invasive infection. In an era before antibiotics and sterility, invasive infection was clearly a threat to life. As such, a very rapid and dramatic recruitment of inflammatory cells and a proliferative/contractile burst of activity to close the wound as quickly as possible were adaptive. The more leisurely pace of tissue regeneration was a luxury that could not be afforded. However, in the modern world, these adaptive responses often lead to the disfigurement and functional disability characteristic of burn scars. What was once functional has become unwanted, in part because of our ability to close wounds with sutures, circumventing the need for a vigorous contractile response following injury.

In the same way that scar formation is not always bad, tissue regeneration is not always good. Peripheral nerve neuromas are dysfunctional and harmful attempts at regeneration of organ systems that have been damaged. They often result in disabling conditions that threaten the livelihood of an entire organism. In these cases, scar formation would be preferable. Indeed, the ablative measures used to treat these neuromas are attempts to prevent further regeneration.

FIGURE 2.1. The different ways organisms and organ systems respond to injuries. Scar formation refers to the patching of a defect with a different or modified tissue (i.e., scar). Tissue regeneration refers to the complete re-creation of the original tissue architecture. Obviously, most processes involve both, but usually one predominates and may be the source of undesirable side effects that we would like to prevent or modify. For cutaneous wounds, scar formation usually predominates (except in the unique situation of fetal wound healing) and is the source of many of the problems plastic surgeons address.

Thus, when analyzing an undesirable or dysfunctional response to injury in a tissue or organ system, it is useful to consider a) what the undesirable portion of the response to injury is and b) whether substitution of a new tissue (scar) or re-creation of the pre-existing tissue (regeneration) is responsible for this undesirable effect. It is important to consider the possible adaptive role the dysfunctional process might have. In the event of a neuroma, the case can be made that the occasional return of protective or functional sensibility following a partial nerve injury is more adaptive and has a survival advantage over the occurrence of complete anesthesia in a peripheral nerve territory. Similarly with respect to fetal wound healing, in the sterile intrauterine environment the predominance of regenerative pathways may be adaptive, whereas for the adult organism existing in a microbe-filled environment, it may not be.

Such an analysis immediately suggests strategies to correct the undesirable end result in a given tissue or organ. If the problem is overexuberant scar formation, then it is likely that measures to decrease scarring would be helpful. However, since this balance is dynamic, efforts at accelerating regeneration might also be effective. And perhaps even better still would be the simultaneous decrease in scar formation and increase in tissue regeneration.

It is clear that the response to injury in different tissues involves different proportions of scar formation and tissue regeneration. By understanding the differences using the approach described above, we may be able to begin to understand why different organs and tissues respond to injuries in very different ways. Just as a corneal ulcer, a myocardial infarction, and a stage IV decubitus ulcer have different functional implications for the organism, the dynamic balance of scarring and regeneration will be different in the attempt to re-establish homeostasis. The failure of either scar formation or regeneration may lead to similar appearing clinical problems that have a completely different underlying etiology. Hopefully, this type of analysis will lead to a more organized approach to the classification and treatment of injuries in a variety of different organ systems. Most importantly, it may suggest strategies for intervention to optimize the response to injury and prevent the undesirable sequelae of wound healing.

SEMANTICS OF WOUND HEALING

The nomenclature of both scientific and clinical wound healing research is at times imprecise and confusing. For example, what is the difference between a chronic wound and a non-healing wound? For purposes of this chapter, several terms should be defined. The vast majority of surgical wounds are incisional wounds that are re-approximated by sutures or adhesives and in the absence of complications will heal “primarily” or by “primary intention.” Generally such wounds heal with a scar and do not require special wound care or the involvement of a specialist in wound healing. This is in contrast to wounds that are not re-approximated (for any reason) and left “open.” The subsequent defect is “filled in” with granulation tissue and then re-epithelialized. This is referred to as healing by secondary intention and generally results in a delay in the appearance of a healed or “closed” wound. Often these wounds require special dressings and treatments (to be discussed in detail in Chapter 3) and have a higher likelihood of progressing to a chronic wound. In the discussion of normal wound healing that follows, we will be discussing healing by secondary intention, although the same phases occur in all wounds.

An acute wound is a wound for which the injury has occurred within the past 3 to 4 weeks. If the wound persists beyond 4 to 6 weeks, it is considered a chronic wound, a term that also includes wounds that have been present for months or years. “Non-healingrecalcitrant,” and “delayed healing” are terms used interchangeably to describe chronic wounds. Wounds that are “granulating” represent the formation of highly vascular granulation tissue during the proliferative phase of healing (see below).

PHASES OF NORMAL WOUND HEALING

The normal mammalian response to a break in cutaneous integrity occurs in three overlapping but biologically distinct phases (Figure 2.2). Following the initial injury, there is an initial inflammatory phase, the purpose of which is to remove devitalized tissue and prevent invasive infection. Next, there is a proliferative phase during which the balance between scar formation and tissue regenerations occurs. Usually, scar formation predominates, although in fetal wound healing an impressive amount of regeneration is possible. Finally, the longest and least understood phase of wound healing occurs in the remodeling phase, whose main purpose is to maximize the strength and structural integrity of the wound.

Inflammatory Phase

The inflammatory phase (Figure 2.3) of wound healing begins immediately following tissue injury. The functional priorities during this phase of wound healing are attainment of hemostasis, removal of devitalized tissues, and prevention of colonization and invasive infection by microbial pathogens, principally bacteria.

Initially, components of the injured tissue, including fibrillar collagen and tissue factor, act to activate the clotting cascade and prevent ongoing hemorrhage. Disrupted blood vessels allow circulating elements into the wound while platelets clump and form an aggregate to plug the disrupted vessels. During this process, platelets degranulate to release growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor β (TGF-β). The end result of the coagulation cascade is the conversion of fibrinogen to fibrin and subsequent polymerization into a mesh. This provisional matrix provides the scaffolding for cell recruitment and attachment required during the subsequent phases of wound healing.

Almost immediately, inflammatory cells are recruited to the wound site. During the initial stages of wound healing, inflammatory cells are attracted by numerous biophysical cues, including activation of the complement cascade, TGF-β released by degranulating platelets, and bacterial degradation products such as lipopolysaccharide.7 For the first 2 days following wounding, there is an impressive infiltration of neutrophils into the fibrin matrix that fills the wound cavity. The primary role of these cells is to remove dead tissue by phagocytosis and prevent infection by oxygen-dependent and oxygen-independent killing mechanisms. They also release a variety of proteases to degrade remaining ECM to prepare the wound for healing. It is important to realize that although neutrophils play a role in decreasing infection during cutaneous wound healing, their absence does not appear to prevent the overall progress of wound healing.8 However, their prolonged persistence in the wound has been proposed to be a primary factor in the conversion of acute wounds into non-healing chronic wounds.9

FIGURE 2.2. The three phases of wound healing (inflammatory, proliferative, and remodeling), the timing of these phases in adult cutaneous wound healing, and the characteristic cells that are seen in the healing wound at these time points.

Monocyte/macrophages follow neutrophils into the wound and appear 48 to 72 hours post-injury. They are recruited to healing wounds primarily by expression of monocyte chemoattractant protein 1. Monocyte/macrophages are a heterogeneous population of cells that critically regulate both early and later stages of wound repair.10 Circulating monocytes traffic to wounds and egress into the tissue to become macrophages. By 3 days post-wounding, they are the predominant cell type in the healing wound. Macrophages phagocytose debris and bacteria, but are especially critical for the orchestrated production of the growth factors necessary for the production of the ECM by fibroblasts and the production of new blood vessels in the healing wound. A partial listing of chemokines, cytokines, and growth factors present in the healing wound is provided in Table 2.1, but the list grows daily. The exact function of each of these factors is incompletely understood, and the literature is filled with contradictory data. However, it is clear that unlike the neutrophil, the absence of monocyte/macrophages has severe consequences for healing wounds.11

FIGURE 2.3. The inflammatory phase of wound healing begins immediately following tissue injury and serves to achieve hemostasis, remove devitalized tissues, and prevent invasive infection by microbial pathogens.

The lymphocyte is the last cell to enter the wound and enters between days 5 and 7 post-wounding. Its role in wound healing is not well defined, although it has been suggested that populations of stimulatory CD4 and inhibitory CD8 cells may usher in and out the subsequent proliferative phase of wound healing.12 Similarly, the mast cell appears during the later part of the inflammatory phase, but again its function remains unclear. Recently, it has become an area of intense research inquiry because of a correlation between mast cells and some forms of aberrant scarring.

Given the consistent and precise appearance of different subsets of inflammatory cells into the wound, it is likely that soluble factors released in a stereotypic pattern underlie this phenomenon. The source of these factors, the upstream regulators for their production, and the downstream consequences of their activity are extraordinarily complex topics and the subject of intense ongoing research. Again in Table 2.1, a partial list of growth factors thought to be important during wound healing is provided. All are targets for the development of therapeutics to either accelerate wound healing or decrease scar formation.5 However, the biologic relevance of any one factor in isolation remains unclear.

Proliferative Phase

The proliferative phase of wound healing is generally accepted to occur from days 4 to 21 following injury. However, the phases of wound healing are not exclusive and have features that overlap. Certain facets of the proliferative phase such as re-epithelialization probably begin almost immediately following injury. Keratinocytes adjacent to the wound alter their phenotype in the hours following injury. Regression of the desmosomal connections between keratinocytes and to the underlying basement membrane frees cells and allows them to migrate laterally. Concurrent with this is the formation of actin filaments in the cytoplasm of keratinocytes, which provides them with the locomotion to actively migrate into the wound. Keratinocytes then move via interactions with ECM proteins (such as fibronectin, vitronectin, and type I collagen) via specific integrin mediators as they proceed between the desiccated eschar and the provisional fibrin matrix beneath (Figure 2.4).

The provisional fibrin matrix is gradually replaced by a new platform for migration: granulation tissue. Granulation tissue is largely composed of three cell types that play critical and independent roles in granulation tissue formation: fibroblasts, macrophages, and endothelial cells. These cells form ECM and new blood vessels, which histologically are the ingredients for granulation tissue. Granulation tissue begins to appear in human wounds by about day 4 post-injury. Fibroblasts are the workhorses during this time and produce the ECM that fills the healing scar and provides a scaffold for keratinocyte migration. Eventually this matrix will be the most visible component of cutaneous scars. Macrophages continue to produce growth factors such as PDGF and TGF-β1 that induce fibroblasts to proliferate, migrate, and deposit ECM, as well as stimulate endothelial cells to form new vessels. During the proliferative phase, the provisional matrix of fibrin is replaced with thinner type III collagen, which will in turn be replaced by thicker type I collagen during the remodeling phase.

Endothelial cells are a critical component of granulation tissue and form new blood vessels through angiogenesis and the newly described process of vasculogenesis, which involves the recruitment and assembly of bone marrow–derived progenitor cells.13 Proangiogenic factors that are released by macrophages include vascular endothelial growth factor, fibroblast growth factor 2, angiopoietin 1, and thrombospondin. The upstream activator of gene transcription of these growth factors may be hypoxia via hypoxia-inducible factor 1αprotein stabilization. The relative importance of these different vascular growth factors and the precise timing of their arrival and disappearance are areas of active investigation. However, it is clear that the formation of new blood vessels and subsequent granulation tissue survival is important for wound healing during the proliferative phase of wound healing.

FIGURE 2.4. The proliferative phase of wound healing occurs from days 4 to 21 post-wounding. During this phase, granulation tissue fills the wound and keratinocytes migrate to restore epithelial continuity.

One interesting element of the proliferative phase of wound healing is that at a certain point all of these processes need to be turned off and the formation of granulation tissue/ECM halted. It is clear that this is a regulated event because once collagen matrix has filled in the wound cavity, fibroblasts rapidly disappear and newly formed blood vessels regress, resulting in a relatively acellular scar under normal conditions. So how do these processes turn off? It seems likely that these events are programmed and occur through the gradual self-destruction of cellular apoptosis. The signals that activate this program are unknown but must involve environmental factors as well as molecular signals. Since dysregulation of this process is believed to underlie the pathophysiology of fibrotic disorders such as hypertrophic scarring, understanding the signals for halting the proliferative phase is of obvious importance for developing new therapeutics for these disabling conditions.

Remodeling Phase

The remodeling phase is the longest component of wound healing and in humans is thought to last from 21 days up to 1 year. Once the wound has been “filled in” with granulation tissue and after keratinocyte migration has re-epithelialized it, the process of wound remodeling occurs. Again, these processes overlap and the remodeling phase likely begins with the programmed regression of blood vessels and granulation tissue described above. Despite the long duration of the remodeling phase and the obvious relevance to ultimate appearance, it is by far the least understood phase of wound healing.

In humans, remodeling is characterized by the processes of wound contraction and collagen remodeling (Figure 2.5). The process of wound contraction is produced by wound myofibroblasts, which are fibroblasts with intracellular actin microfilaments capable of force generation and matrix contraction.14 It remains unclear whether the myofibroblast is a separate cell from the fibroblast or whether all fibroblasts retain the capacity to “trans-differentiate” to myofibroblasts under the right environmental conditions. Myofibroblasts contact the wound through specific integrin-mediated cell–matrix interactions with the dermal environment.

Collagen remodeling is also characteristic of this phase. Type III collagen is initially laid down by fibroblasts during the proliferative phase, but over the next few weeks to months this will be replaced by type I collagen. This slow remodeling phase is largely mediated by a class of enzymes known as matrix metalloproteinases that are secreted in large part by macrophages, fibroblasts, and endothelial cells.15 The breaking strength of the healing wound improves slowly during this process, reflecting the turnover in collagen subtypes and increased collagen cross-linking. At 3 weeks, the beginning of the remodeling phase, wounds have only about 20% of the strength of unwounded skin and will ultimately only possess 70% to 80% of the breaking strength of unwounded skin at 1 year.

ABNORMAL RESPONSE TO INJURY AND ABNORMAL WOUND HEALING

Just as it is overly simplistic to consider all the different responses to injury seen in different tissues as simply “wound healing,” it is naïve to try to classify all the manifestations of abnormalities in this process as simply “abnormal wound healing.” To more accurately classify all the different types of abnormal wound healing, it is useful to consider the balance between attempts to replace tissue defects with new, substitute tissues (scar formation) against the re-creation of the original tissue in situ (regeneration), as illustrated in Figure 2.1. It is also helpful to determine where within the normal phases of wound healing the problem occurs. The goal is to understand each abnormal process in terms of dynamic balance and to propose therapeutic strategies to restore homeostasis on a cellular, tissue, and organ level.

Such a process is not merely a semantic exercise but has potential therapeutic implications. Thus, although a corneal ulcer, a peripheral neuroma, and stage IV sacral decubitus ulcer are all examples of abnormal healing, the treatment as guided by an understanding of the underlying mechanism will be completely different. Thus, for a corneal ulcer, which represents a defect in epithelial regeneration, growth factor therapy would make sense to augment the potential for regeneration, whereas it would make less sense for a defect such as a peripheral neuroma. For a neuroma, treatments aimed at preventing nerve regeneration would seem to make more sense. In the following paragraphs, we will attempt to classify the various types of abnormal wound healing using the dynamic balance between scar formation and regeneration. It is hoped that such an analysis might elucidate and clarify new therapeutic opportunities targeting one component or the other, as illustrated in Figure 2.1.

FIGURE 2.5. The remodeling phase of wound healing is the longest phase and lasts from 21 days to 1 year. Remodeling, though poorly understood, is characterized by the processes of wound contraction and collagen remodeling.

Inadequate Regeneration Underlying an Abnormal Response to Injury

The classic example of this is found in central nervous system injuries that occur following traumatic injury or following tumor ablation. The response to injury in these cases is usually characterized by virtually no restoration or recovery of functional neural tissue. The absence of neural regeneration is compensated by a normal physiologic process of replacement with scar tissue, but in most cases this process does not appear excessive or overexuberant. Although efforts to decrease scar formation have been attempted, it is currently thought that these will be ineffective unless neural regeneration can also be achieved. Thus, currently efforts are focused on strategies to increase regeneration of neural tissue to treat this abnormal response to injury.16 Current modalities under investigation include the use of implanted neural stem/progenitor cells or the use of developmental morphogens to recapitulate the processes of neural development. Techniques to decrease neural scar formation might also be useful to provide a window of opportunity for regeneration to occur, but they are unlikely to be successful in and of themselves. Other examples of inadequate regeneration would include bone nonunions and corneal ulcers.

Inadequate Scar Formation Underlying an Abnormal Response to Injury

Many examples of impaired wound healing seen by plastic surgeons belong in this category. In most cases, these diseases result from a failure to replace a tissue defect with a substitute patch of scar (i.e., inadequate scar formation). In these conditions, stable scar tissue would be sufficient to restore cutaneous integrity and eliminate the pathology. Regeneration of the skin, although perhaps ideal, is not required for an adequate functional outcome. Examples of these types of conditions include diabetic foot ulcers, sacral decubiti, and venous stasis ulcers. In all these cases, restoration of cutaneous integrity would be sufficient, and as such, efforts must be made to understand and correct the defects in scar formation that occur in these disease states.

Once the defect in scar formation is understood, therapeutics can be rationally designed to correct these defects. At times, it is useful to subdivide the scar formation defects further and examine whether the primary defect occurs in the inflammatory, proliferate, or remodeling phases of wound healing. For instance, in humans and experimental models, diabetic ulcers occur because of defects in the inflammatory and proliferative phases of wound healing. Accordingly, therapeutics are targeted toward these phases.17 In contrast, wounds occurring because of vitamin C depletion (i.e., scurvy) are due to abnormal collagen cross-linking, which occurs during the remodeling phase of wound healing. Therapeutics should be directed at this later phase. While in both cases therapeutic efforts are focused on correcting defects in scar formation (as opposed to augmenting tissue regeneration), the therapeutic targets will be different.

Excessive Regeneration Underlying an Abnormal Response to Injury

These situations are relatively rare. In these cases, pathways of tissue regeneration lead to the re-creation of the absent tissue, but there are functional problems reintegrating the tissue into the systemic physiology. They often occur in peripheral nerve–like tissue, such as peripheral nerve regeneration leading to neuroma. Other examples might include the hyperkeratosis that occurs in cutaneous psoriasis or granuloma formation in healing wounds. It seems plausible that many conditions we consider “precancerous” are the result of overexuberant attempts at tissue regeneration following minor traumatic insults. This then leads to disordered and uncontrolled growth. Clearly, in these situations, scar formation would be preferable to regeneration because of the risk of loss of growth control and possible transformation to overt cancer.

In these disease states, therapeutic measures are targeted toward decreasing cellular proliferation and blocking or impeding the aberrant regenerative pathways. Irritant strategies to maximize scar formation may also play a role, as when alcohol is injected into a neuroma. The goal is to limit the ability of the tissue to activate pathways leading to regeneration. It is sobering to realize that although much current effort is focused on maximizing tissue regeneration, there are circumstances where this already occurs and has proven to be dysfunctional. It also illustrates the need to strictly control the growth and development of tissue generation using emerging stem and progenitor cell technologies.

Excessive Scar Formation Underlying an Abnormal Response to Injury

When these conditions affect the skin, they are very commonly treated by plastic surgeons, but they can occur elsewhere as in pulmonary fibrosis or cirrhosis. “Excessive” cutaneous scar formation remains a poorly understood and ubiquitous disease for which there are few treatment options. Abnormal scarring is classified as either hypertrophic scarring or keloid formation. Both are manifestations of overexuberant scarring, although the upstream etiology is probably different.18 Keloids are less common and have a genetic component that limits them to <6% of the population, primarily the black and Asian populations. Histologically, keloids are differentiated by the overgrowth of dense fibrous tissue beyond the borders of the original wound, with large thick collagen fibers composed of numerous fibrils closely packed together. Hypertrophic scars are also characterized by the formation of dense collagen fibers following injury but, in contrast to keloids, do not extend beyond the original wound margins. They are more prone to forming disabling contractures and are a near-universal outcome following extensive deep burn injury.

The etiology and pathophysiology of both hypertrophic scarring and keloid formation remain unknown. Many theories have been proposed to account for the fibroproliferation observed in hypertrophic scar and keloid formation, including mechanical strain, inflammation, bacterial colonization, and foreign body reaction. Unfortunately, investigation of the mechanisms underlying these diseases has been hindered by the absence of animal models that reproduce the characteristics of human overscarring. Decreasing the process of scar formation is the prime goal of therapy for both disease states. Modalities employed include steroid injections, pressure therapy with silicone sheeting, and external beam irradiation. However, with current treatment modalities, recurrence rates approach 75%.19

The prolonged secretion of inflammatory cytokines has been shown to induce fibrosis in numerous in vitro and animal models. Thus, researchers have long sought to manipulate the cytokine environment to prevent scar formation. Most recently, a phase III clinical trial based on the use of recombinant human TGF-β3 (an antagonist of profibrotic TGF-β1) to improve scar revision outcomes was terminated after failing to reach primary endpoints. Given the known complexity of wound healing, it should not be surprising that targeting a single cytokine would be inadequate to reduce organ-level fibrosis.

Recent research has also implicated a key role for mechanical force in promoting both hypertrophic scarring and keloid formation.20,21 Plastic surgeons have long recognized the importance of tension during wound healing, and several current treatments for scarring (e.g., silicone sheeting and compression garments) may have a “mechanomodulatory” mechanism of action. Mechanical cues are known to activate fibroproliferative pathways in skin cells, and the underlying molecular pathways are only beginning to be uncovered in vivo.22 Further, the ability of physical forces to control clinical outcomes is demonstrated by the incorporation of negative pressure wound therapies in modern wound treatment algorithms.23 Future strategies to prevent scar formation may in fact be aimed at manipulating the mechanical and physical cues controlling wound repair and fibrosis.

EMERGING CONCEPTS IN WOUND HEALING

Human skin must continually adapt and renew during development and in response to injury and disease. This suggests the intrinsic ability of the skin to “regenerate.” Several stem cell populations have been identified in the skin and are increasingly studied as potential therapies for wound repair. These progenitor populations include epidermal stem cells, hair follicle stem cells, and adipose-derived stem cells that have the capacity to restore almost all skin compartments.2,24,25 Further, studies in mammalian digit tip regeneration suggest that the biologic machinery necessary to regrow damaged soft tissues may already be present in adults in the form of tissue-specific adult stem cells.26 Thus, it is clear that stem cells play a key role in normal wound healing; the question for researchers is how to exploit these powerful cell populations to promote cutaneous repair in disease states.

Another component of the wound environment that has been largely overlooked is the ECM. As stated earlier, wound remodeling is the least well understood phase of wound healing but appears to involve regulation of extracellular enzymes that control the structural architecture of the ECM. It has been shown that the ECM is a dynamic and active component of the wound that can directly control cell activity,27 resulting in a “dynamic reciprocity” between cells and their immediate environment that maintains skin homeostasis.28 This concept underlies the development of tissue engineering strategies to deliver and re-create the precise biophysical cues that promote biologic programs conducive to healing.29,30

The three traditional phases of wound healing were established decades ago, and since then, research in wound repair has continued to build upon these fundamental concepts. However, as modern research continues to elucidate the complexity of tissue repair processes, we will undoubtedly need to redefine what normal wound healing is in terms beyond just inflammatory cell trafficking and a handful of cytokines. Traditional approaches to wound healing will also need to be integrated with our improved understanding of the molecular pathophysiology of aberrant cutaneous repair. Plastic and reconstructive surgeons need to be intimately familiar with these evolving concepts to ensure the optimal care of our patients.

CONCLUSIONS

In this chapter, a theoretical framework has been proposed with which to understand and classify the normal responses to injury that occur in different tissues and different species. These responses can be conceptualized as favoring replacement of injured tissue with a patch, otherwise known as scar formation, or recapitulating developmental processes to duplicate the original architecture, otherwise referred to as regeneration. The dynamic balance between these two processes may underlie the myriad abnormal responses to injury that occur in human disease states. It is hoped that such a framework will suggest new therapeutic strategies to correct imbalances, by either augmenting or suppressing one component or the other. This may provide a basis for accelerated progress in the care of patients with abnormal or dysfunctional responses to injury that result in human disease.

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