Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. Keywords: wound healing, inflammation, proliferation, tissue remodeling The wound-healing process consists of four highly integrated and overlapping phases: hemostasis, inflammation, proliferation, and tissue remodeling or resolution (Gosain and DiPietro, 2004). These phases and their biophysiological functions must occur in the proper sequence, at a specific time, and continue for a specific duration at an optimal intensity (Table 1; Mathieu et al., 2006). There are many factors that can affect wound healing which interfere with one or more phases in this process, thus causing improper or impaired tissue repair. Normal Wound-healing Process
Wounds that exhibit impaired healing, including delayed acute wounds and chronic wounds, generally have failed to progress through the normal stages of healing. Such wounds frequently enter a state of pathologic inflammation due to a postponed, incomplete, or uncoordinated healing process. Most chronic wounds are ulcers that are associated with ischemia, diabetes mellitus, venous stasis disease, or pressure. Non-healing wounds affect about 3 to 6 million people in the United States, with persons 65 years and older accounting for 85% of these events. Non-healing wounds result in enormous health care expenditures, with the total cost estimated at more than $3 billion per year (Mathieu et al., 2006; Menke et al., 2007). Laboratory investigations and clinical studies have yielded a wealth of information about both normal and impaired wound healing. More recently, a great deal of research has been directed at understanding the critical factors that influence poorly healing wounds. While much remains to be learned, these studies may lead to therapeutics that will promote proper tissue repair and improve impaired wound healing. This review will discuss the many different factors that affect cutaneous wound healing and the potential cellular and molecular mechanisms involved. Wound healing is a dynamic process consisting of four continuous, overlapping, and precisely programmed phases. The events of each phase must happen in a precise and regulated manner. Interruptions, aberrancies, or prolongation in the process can lead to delayed wound healing or a non-healing chronic wound. In adult humans, optimal wound healing involves the following the events: (1) rapid hemostasis; (2) appropriate inflammation; (3) mesenchymal cell differentiation, proliferation, and migration to the wound site; (4) suitable angiogenesis; (5) prompt re-epithelialization (re-growth of epithelial tissue over the wound surface); and (6) proper synthesis, cross-linking, and alignment of collagen to provide strength to the healing tissue (Gosain and DiPietro, 2004; Mathieu et al., 2006). The first phase of hemostasis begins immediately after wounding, with vascular constriction and fibrin clot formation. The clot and surrounding wound tissue release pro-inflammatory cytokines and growth factors such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF). Once bleeding is controlled, inflammatory cells migrate into the wound (chemotaxis) and promote the inflammatory phase, which is characterized by the sequential infiltration of neutrophils, macrophages, and lymphocytes (Gosain and DiPietro, 2004; Broughton et al., 2006; Campos et al., 2008). A critical function of neutrophils is the clearance of invading microbes and cellular debris in the wound area, although these cells also produce substances such as proteases and reactive oxygen species (ROS), which cause some additional bystander damage. Macrophages play multiple roles in wound healing. In the early wound, macrophages release cytokines that promote the inflammatory response by recruiting and activating additional leukocytes. Macrophages are also responsible for inducing and clearing apoptotic cells (including neutrophils), thus paving the way for the resolution of inflammation. As macrophages clear these apoptotic cells, they undergo a phenotypic transition to a reparative state that stimulates keratinocytes, fibroblasts, and angiogenesis to promote tissue regeneration (Meszaros et al., 2000; Mosser and Edwards, 2008). In this way, macrophages promote the transition to the proliferative phase of healing. T-lymphocytes migrate into wounds following the inflammatory cells and macrophages, and peak during the late-proliferative/early-remodeling phase. The role of T-lymphocytes is not completely understood and is a current area of intensive investigation. Several studies suggest that delayed T-cell infiltration along with decreased T-cell concentration in the wound site is associated with impaired wound healing, while others have reported that CD 4+ cells (T-helper cells) have a positive role in wound healing and CD8+ cells (T-suppressor-cytotoxic cells) play an inhibitory role in wound healing (Swift et al., 2001; Park and Barbul, 2004). Interestingly, recent studies in mice deficient in both T- and B-cells have shown that scar formation is diminished in the absence of lymphocytes (Gawronska-Kozak et al., 2006). In addition, skin gamma-delta T-cells regulate many aspects of wound healing, including maintaining tissue integrity, defending against pathogens, and regulating inflammation. These cells are also called dendritic epidermal T-cells (DETC), due to their unique dendritic morphology. DETC are activated by stressed, damaged, or transformed keratinocytes and produce fibroblast growth factor 7 (FGF-7), keratinocyte growth factors, and insulin-like growth factor-1, to support keratinocyte proliferation and cell survival. DETC also generate chemokines and cytokines that contribute to the initiation and regulation of the inflammatory response during wound healing. While cross-talk between skin gamma-delta T-cells and keratinocytes contributes to the maintenance of normal skin and wound healing, mice lacking or defective in skin gamma-delta T-cells show a delay in wound closure and a decrease in the proliferation of keratinocytes at the wound site (Jameson and Havran, 2007; Mills et al., 2008). The proliferative phase generally follows and overlaps with the inflammatory phase, and is characterized by epithelial proliferation and migration over the provisional matrix within the wound (re-epithelialization). In the reparative dermis, fibroblasts and endothelial cells are the most prominent cell types present and support capillary growth, collagen formation, and the formation of granulation tissue at the site of injury. Within the wound bed, fibroblasts produce collagen as well as glycosaminoglycans and proteoglycans, which are major components of the extracellular matrix (ECM). Following robust proliferation and ECM synthesis, wound healing enters the final remodeling phase, which can last for years. In this phase, regression of many of the newly formed capillaries occurs, so that vascular density of the wound returns to normal. One critical feature of the remodeling phase is ECM remodeling to an architecture that approaches that of the normal tissue. The wound also undergoes physical contraction throughout the entire wound-healing process, which is believed to be mediated by contractile fibroblasts (myofibroblasts) that appear in the wound (Gosain and DiPietro, 2004; Campos et al., 2008). The role of stem cells (SC) in cutaneous wound healing and tissue regeneration is a topic of increasing research attention, with a focus on the role of adult stem cells such as epidermal stem cells and bone-marrow (BM)-derived cells (BMDCs). Epidermal stem cells reside in the bulge area of hair follicles and in the basal layer of the epidermis and give rise to the keratinocytes that migrate andre-epithelialize wounds. Normal skin is also a target organ for BMDCs. Two main stem cell populations are present in the bone marrow: hematopoietic SC (HSC) and mesenchymal SC (MSC). BM-MSCs are able to differentiate into a variety of cell types, including adipocytes, osteoblasts, chondrocytes, fibroblasts, and keratinocytes (Cha and Falanga, 2007; Rea et al., 2009). Endothelial progenitor cells (EPCs) derived from the HSC lineage are key cells that contribute to neovascularization. Both BM-MSCs and EPCs are involved in the cutaneous wound-healing process. Wound-induced hypoxia triggers the mobilization of bone marrow EPCs to the circulation, playing a significant role in the process of neovascularization (Wu et al., 2007; Liu and Velazquez, 2008; Rea et al., 2009). Several different cell types are involved in the wound-healing process, and, as described above, the cellular activities of any particular cell type may also vary during different stages of repair. The complexity and coordination of the healing process are major hurdles to therapeutic approaches, since any therapeutic must effectively be sequenced to the appropriate stage. Wound healing is a complex biological process that consists of hemostasis, inflammation, proliferation, and remodeling. Large numbers of cell types—including neutrophils, macrophages, lymphocytes, keratinocytes, fibroblasts, and endothelial cells—are involved in this process. Multiple factors can cause impaired wound healing by affecting one or more phases of the process and are categorized into local and systemic factors. The influences of these factors are not mutually exclusive. Single or multiple factors may play a role in any one or more individual phases, contributing to the overall outcome of the healing process. The authors thank Dr. Wendy Cerny for helpful comments and discussion. This publication was supported by Grants RO1-GM50875 (LAD) and P20-GM078426 (LAD). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or the NIH.
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The nurse is providing care to a patient who is experiencing delayed healing of a surgical wound
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