Macrophage manipulation for improved wound healing
By Liza G. Ovington, PhD, CWS
President
Ovington & Associates
Ft. Lauderdale, FL
Macrophages are large, mononuclear phagocytic cells that serve as part of the nonspecific defenses of the immune system. Their behavior is multifunctional, and many of their actions play an important part in the healing process.
The macrophage's job is to recognize anything that is not endogenous tissue, be it devitalized tissue, other cells such as bacteria, or foreign materials. Once the macrophage recognizes such an intruder, it will engulf or phagocytose it. If there is an adequate supply of oxygen, the macrophage will then create oxygen free radicals, with which it carries out the process of oxidative killing. They also produce enzymes to lyse the engulfed material, thereby clearing the injury site for new tissue formation. These aspects of the macrophage's behavior are vital in the inflammatory phase of healing.
In addition to their phagocytic activities, macrophages secrete substances that promote the formation of new tissue. Specifically, they secrete growth factors that stimulate the formation of new blood vessels, such as transforming growth factor (TGF) alpha and vascular endothelial growth factor (VEGF) endothelin.1 The macrophage is especially stimulated to secrete these factors when tissue is hypoxic, or when they are needed most. In fact, the macrophage is the cell most able to function under severely hypoxic conditions. The process of angiogenesis is critical to the proliferative phase of wound healing. By stimulating angiogenesis, the macrophage sets the stage for new tissue to survive and facilitates the transition from the inflammatory phase of healing to the proliferative phase. The macrophage then goes on to secrete factors (recombinant human platelet-derived growth factor [PDGF], TGF beta) that cause fibroblasts to migrate to the injury site, to proliferate, and to synthesize collagen. By "calling" fibroblasts into the site of injury and exerting some influence on their productivity, the macrophage promotes the formation of granulation tissue.
With all of its activities, the macrophage is similar to a foreman on a building construction site; it clears the site for construction, makes sure power lines are in place to support the construction, and then orders around the guys actually doing the construction.
In short, the macrophage is vital to successful healing, even essential. Studies in rabbits have shown that if wounds are made macrophage-deficient, healing does not occur.1 More specifically, the study showed that in the absence of macrophages, fibroblasts were greatly delayed in their arrival at the wound site. Once there, their rate of proliferation was slower than in control wounds where macrophages were present.
Other studies have set out to stimulate the macrophage to do more of what it does naturally and thereby enhance healing. Theoretically, if macrophages were stimulated to increase production and secretion of growth factors, wound healing would be enhanced.
One material known to stimulate macrophages is a complex carbohydrate called beta glucan. Stimulation of animal wounds with topical glucan reduced the time to complete healing by 18% compared to unstimulated control wounds in the same animal.2
One research group found that macrophage stimulation with glucan in the early stages of wound healing in rats resulted in increased wound tensile strengths.3 By applying the glucan early in the wound healing process, any effect on healing was thought not to be simply a result of increased collagen synthesis (via macrophage stimulation of fibroblast arrival and activity). Analysis of the healed tissues showed evidence of increased collagen crosslinking in the glucan-treated wounds. The exact mechanism of the macrophage's effect on collagen crosslinking is uncertain.
A commercial product that seeks to utilize the effects of glucan on macrophages for wound healing is the Beta-glucan product line (Brennen Medical, Inc., St. Paul, MN) including BGC Matrix and Glucan II. BGC Matrix combines beta glucan with collagen hydrocolloid matrix, whereas Glucan II contains beta glucan alone.
Another commercial product that claims to take advantage of macrophages is the Carrasyn line of hydrogel products containing a constituent of aloe called acemannan (Carrington Laboratories, Irving, TX). Acemannan is a complex carbohydrate that has been shown in vitro to stimulate macrophages to produce more growth factors in a dose-dependent fashion.4
Biafine Wound Emulsion (KCI, San Antonio), which has been shown to recruit macrophages to the wound site when applied topically, is another product to exploit the macrophage for healing.5
Supplementing 'inactive' macrophages
Perhaps more exciting than stimulation of macrophages already in wounds is the application of "extra" macrophages to wounds to enhance repair. Recent studies of macrophages from wound biopsies of chronic leg ulcers found that these cells exhibited no evidence of activation and postulated that the chronic wound microenvironment suppresses macrophage function, potentially leading to inappropriate amounts and ratios of growth factors for optimal repair.6 What if such "inactive" macrophages could be supplemented in the wound by healthy, active macrophages to start directing the construction job?
A study in 1989 addressed this question by injecting old mice who exhibited slow healing due solely to age (as opposed to disease) with additional macrophages from other mice.7 They found that wound healing was accelerated. When the donor mice were younger mice, the healing acceleration was even greater. The same investigator has taken this concept of exogenous macrophage application to humans and has more recently published results of pressure ulcer treatment with macrophages prepared from a blood unit. (See related story in Wound Care, May 1998, pp. 57-58.) Seventy-two patients with 131 pressure ulcers were treated with macrophages (one application) and their healing compared to 127 patients with 248 pressure ulcers treated with conventional therapies and no macrophages. Twenty-seven percent of the macrophage-treated ulcers healed, compared to only 6% of the control ulcers.
The tissue macrophage is a multifaceted cell that is intimately and inextricably involved in multiple phases of the wound healing process through its phagocytic, angiogenic, and fibroblast-modulating activities. There are experimental data in animals and humans to suggest that these macrophage activities may be exploited to enhance healing in chronic wounds (that may suppress the activity of endogenous macrophages), in the wounds of the aged, or in iatrogenic wounds. In addition to faster healing, there is suggestive evidence that macrophages may result in a stronger healed wound and thereby lead to fewer wound recurrences. Stimulation of existing macrophages or topical application of additional exogenous macrophages to the wound may achieve enhancement of healing and may present an exciting new therapy in addition to advanced dressings, bioengineered tissue products, and recombinant growth factors.
References
1. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78:71-100.
2. Wolk M, Danon D. Promotion of wound healing by yeast glucan evaluated on single animals. Med Biol 1985; 63:73-80.
3. Browder W, Williams D, Lucore P, et al. Effect of enhanced macrophage function on early wound healing. Surgery 1988; 104:224-230.
4. Zhang L, Tizard IR. Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe vera gel. Immunopharmacology 1996; 35:119-128.
5. Coulomb B, Friteau L, Dubertret L. Biafine applied on human epidermal wounds is chemotactic for macrophages and increases the IL-1/IL-6 ratio. Skin Pharmacol 1997; 10:281-287.
6. Moore K, Ruge F, Harding KG. T lymphocytes and the lack of activated macrophages in wound margin biopsies from chronic leg ulcers. Br J Dermatol 1997; 137:188-194.
7. Danon D, Kowatch MA, Roth GS. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci USA 1989; 86:218-220.
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