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^,4^,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.

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.

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.

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-healing, recalcitrant,” 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).

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.