Phases of Wound Healing

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Wound healing has traditionally been divided into three phases: inflammatory, granulation tissue formation/proliferative, and remodeling (32). The division is arbitrary and the phases overlap. However, this classification serves to highlight different components of a very complex process; in this section we present additional aspects of altered wound repair in aging utilizing the guidelines provided by this division.

4.2.1. Inflammatory Phase

After injury, the initial inflammatory phase of wound repair is characterized by formation of a fibrin clot, activation of platelets with subsequent release of platelet-derived factors, and an influx of macrophages followed closely by lymphocytes. The activation of circulating and resident cell populations results in the release of soluble mediators such as tumor necrosis factor-a (TNF-a), interleukins, nitric oxide (NO), and growth factors. In addition, epithelial closure (epithelialization) and wound contraction begin in this early stage.

There is a consensus that the inflammatory response is altered with age. However, whether this response is increased or decreased depends on the aspect of inflammation that is examined (for review see ref. 7). Older studies have shown that aging increases the aggregation of platelets and the adhesion of endothelial cells to monocytes (73-75), changes that could enhance the initial stages of the inflammatory response. Moreover, aged mononuclear cells have been shown to produce increased amounts of the inflammatory mediators interleukin-6 (IL-6) and TNF-a in response to stress (76). By contrast, aged cells release less of the potent vasoactive messenger NO (21). Old skin clearly shows a decrease in the number and function of APCs such as Langerhans cells and mast cells, thereby leading to impaired cell-mediated immunity in stimulated tissues. With age there is a delay in the appearance of monocytes and macrophages during wound repair (40). Age decreases neutrophil respiratory burst activity and the capacity for glucose utilization in lymphocytes and macrophages (77,78). Danon et al. (79) demonstrated a functional decline in macrophages during wound healing in aged mice. In their study the application of peritoneal macrophages from young mice to the cutaneous wounds of the aged mice accelerated the repair to rates comparable with those of young animals. Although the number of lymphocytes in the circulation is unchanged, there is a defect in activation and a subsequent delay in the appearance of immunoreactive cells in inflamed tissues in aged humans (80,81).

In summary, the inflammatory phase of wound healing in the aged is associated with an increase in platelet aggregation and endothelial-monocyte adhesion. With the exception of NO, the release of inflammatory mediators is maintained and may be increased. However, the number and function of macrophages and lymphocytes in aged skin is reduced, and their appearance in wounds is delayed.

Epithelialization is critical for wound closure and is dependent on both proliferation and migration. Animal studies have demonstrated that the rate of reepithelialization in the palatal mucosa of aged rats (82) and in partial-thickness wounds in old mice is decreased (83). In humans, Grove and colleagues (5,84) showed delayed epithelialization and epithelial turnover in an older cohort 65-75 yr of age; as expected, there was significant variability among the aged individuals. Holt et al. (85) found a more rapid rate of reepithelialization of superficial split-thickness wounds in subjects ages 18-55 yr as compared with a group of patients over age 65. Recently it has been noted that in addition to reduced proliferation, keratinocytes from aged donors demonstrate significantly slowed migration on type I collagen (25). Thus, under the stress of a wound, both the proliferation and migration of keratinocytes are decreased in aged skin.

4.2.2. Proliferative Phase

The granulation tissue formation or proliferative phase involves nearly every cell type in the skin. Fibroblasts from the surrounding dermis migrate into the injured site and are responsible for contraction, proliferation, and deposition of ECM. Keratinocytes continue the process of reepithelialization. Dermal microvascular endothelial cells, in conjunction with supporting cells such as fibroblasts, enhance blood flow via the process of angiogenesis.

Fibroblasts migrate into the wound area in response to growth factors and signals from the provisional matrix (fibrin and fibronectin) approx 2-4 d after injury. Their major role is the synthesis of an ECM comprising primarily collagen. Whereas fibroblasts deposit type III collagen as part of the provisional matrix early in wound repair, it is their subsequent secretion of type I collagen that provides a structural support for healing. This biosynthetic function is compromised in the wounds of aged persons and may be owing, in part, to a lack of TGF-P1. In addition to secretion of ECM, fibroblasts are the major cell type responsible for wound contraction. Older experimental studies in rabbits, rats, and dogs indicate that in older as compared with younger animals the time before initiation of wound contraction is lengthened, the rate of contraction is lower, and the ultimate degree of contraction is less (for review see ref. 7). In general, the changes in fibroblast function during wound repair in aging are as follows: proliferation is decreased, migration is often slowed, the capacity to synthesize growth factors (such as TGF-P1 and VEGF) declines, and the response to exogenous growth factors is often preserved (19,21,24,66,86).

Capillaries in the skin comprise microvascular endothelial cells. In the basal state there are fewer capillaries in aged skin (4). Delayed angiogenesis, the formation of new capillaries from existing capillaries, is thought to contribute to slowed wound healing in aging. Holm-Pedersen (see refs. 33,34, and 87) was among the first to report that the rate of capillary growth in wounded tissues was decreased in older animals. This decline in neovascularization has been attributed to both decreased endothelial cell proliferation and migration. Other age-related defects in endothelial cell behavior include increased adhesion to leukocytes, enhanced response to TNF-a, and greater IL-1 production (7,74,75). Several studies have specifically examined delayed angiogenesis in aged animals and have found, as expected, reduced levels of angiogenic factors such as TGF-P1 and VEGF (21,65). Replacement of these deficient factors increased angiogenesis (21,86). The extrapolation to enhanced wound repair as a direct result of increased neovascularization (as opposed to the numerous other changes induced by the application of these angiogenic factors) remains to be proven.

4.2.3. Remodeling Phase

The remodeling phase involves continued proliferation of fibroblasts and deposition of newly synthesized matrix (termed fibroplasia), completed neovascularization, and formation of mature scar. Collagen (primarily type I) is produced and remodeled throughout this phase, which can last as long as 1 to 2 yr.

Wounds in the aged produce less scarring as compared with young subjects (31). Furthermore, hyperproliferative wound-healing disorders such as keloids and hypertrophic scars are rare in the older population. This is a result, at least in part, of reduced levels of TGF-P in the wounds of the aged. As noted previously, TGF-P is known to enhance net collagen deposition both by increasing its synthesis and by decreasing its degradation. The latter is a result of the effect of TGF-P 1 on increasing the secretion of TIMP at the same time it inhibits the production of the primary collagenase, MMP-1 (65,88). In fact, in an experimental study, the use of neutralizing TGF-P antibody was able to prevent excessive scar formation in adult wounds (89). Consistent with these data, Ashcroft et al. (31) have shown that treatment with topical estrogen accelerated healing, owing to increased expression of TGF-P 1, but resulted in decreased scar quality.

There is a lack of controlled studies of the mechanical properties of healing wounds in the aged. The tensile strength of a wound reflects the organization of the remodeling process and is related to the wound's thickness. By contrast, breaking strength is purely a measure of the ability of a wound to resist disruption. In the past, uncontrolled observations of human postsurgical wounds have noted an increased rate of wound disruption with age, but there was no accounting for concurrent morbidity (90). Animal studies are difficult to interpret because of differences in skin thickness among rodents (whereas mice develop a thinner skin with age, certain strains of rats do not), variability in the definition of mechanical disruption, confounding by other interventions, and small numbers. It is now accepted that wounds in the healthy aged have adequate tensile strength despite an intrinsic decrease in the rate of collagen synthesis relative to the young. Indeed, normal human skin maintains extensibility to the seventh decade; this is in contrast to elasticity, which decreases from an earlier age (91). In both the young and aged, it is important to remember that the tensile strength of a healed wound will never be more than 80% of that of normal, uninjured skin.

In summary, in the absence of comorbidities, there is no conclusive evidence that the mechanical properties of healed wounds in the aged differ significantly from those of the young, but there are no data on very old humans.

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