Wound Healing: A Review II. Environmental Factors Affecting Wound Healing SHELDON V. POLLACK, M.D.

A variety of factors, both intrinsic and extrinsic, may influence the healing of wounds. Some of these influences are environmental in nature and subject to advantageous manipulation by the practitioner. In this article, the role of humidity, temperature, infection and oxygen tension on the process of wound healing will be discussed.

We r e v i e w e d the biology of wound healing in a preceding article.1 Here we review numerous influ­ ences that may modify this natural process, namely, environmental factors, like humidity and temperature, infection, and oxygen tension. THE ROLE OF HUMIDITY

Covered wounds epithelize much more quickly than those left uncovered and allowed to desiccate.2 Gener­ ally, when wounds are left uncovered, epidermal cells must migrate under dry crusts or scabs and over fi­ brous tissue below. Under occluded conditions in which the surface of the wound remains moist, epidermal cells are able to migrate more readily, wherewith epithelization is more rapid (Fig. 1). Moisture in open wounds may be promoted by the use of suitable dressings. A hermetically occlusive dressing, as with polyethylene film, will maintain a warm, moist environment at a wound surface, but such a dressing is not without risk of sepsis because the dilute serous exudate that is likely to accumulate may act as a suitable medium for bacterial culture. Macera­ tion of tissues from hermetic occlusion is also likely to occur. Furthermore, it is difficult to keep this type of dressing in place on wounds that produce excessive exudate. It is more advantageous if gas exchange oc­ curs between the wound surface and the external envi­ ronment. Consequently commercially available dress­ ings that provide semi-occlusive cover by means of microporous and absorbant materials are mechanically Dr. Pollack is Clinical Instructor in Dermatology, New York Uni­ versity School of Medicine, New York, New York. Address reprint requests to Dr. Sheldon Pollack, Chemosurgery Unit, Department of Dermatology, New York University Medical Center, 530 First Avenue, New York, New York 10016.

protective, absorptive of excessive exudate and prop­ erly humidifying. In this way passage of water vapour and gases proceeds readily and contamination by bac­ teria and foreign bodies is minimized3. It is important, however, that dressing materials be such that they do not adhere to wound surfaces because then epithelial cells that have migrated may be torn away with each change of dressing. In studies of shallow cutaneous wounds in the domestic pig, Winter3 found that all dressing materials he used, some advertised as being nonadherent, did indeed adhere to wounds. For example, he found that with the tulle-gras type of dressing material, migrating epidermal cells became enmeshed in the fabric portion of the dressing material because the agent impregnated in the fabric to prevent adherence tended to melt away, leaving the bare fabric lying directly on the wound surface. On removing such dressings, fresh damage was caused to the wound. Another type of material tested was the occlusive-film type of dressing material with perforations to permit drainage into an absorbant backing. With this material, Winter4 found that exu­ date dried in the perforations, causing it to become strongly adherent to the wound surface. Histological sections of wounds covered in this way showed regu­ larly spaced areas of dehydrated dermis corresponding to the perforations in the film. Fisher and Maibach5 conducted a study in which four dressing materials, namely, 1) an occlusive adhesive tape, 2) the adhesive backing alone from this tape, 3) a less occlusive adhe­ sive tape, and 4) an occlusive non-adhesive film were used to cover areas of normal and stripped skin for periods of two to six days. All of these materials de­ creased transepidermal water loss, increased cellular migration, and possibly decreased keratinization.

J. Dermatol. Surg. Oncol. 5:6 June 1979

477

WOUND HEALING: A REVIEW

occlusive dressing

no dressing normal scab

• moist exudate

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FIGURE 1. Comparison o f the mode o f epidermal regeneration in shallow skin wounds under exposed and occlusive conditions. (Reproduced with permission from Winter, G. D. Epidermal regeneration studied in the domestic pig. In: Maibach, H. I., and Rovee, D. T., eds. Epidermal Wound Healing. Chicago, Year Book Medical Publishers, © 1972, p. 108.)

Many surgeons do not consider dressings for sutured wounds important and some prefer to leave such su­ tured wounds open to the air postoperatively. Never­ theless, when sutured wounds are allowed to dehy­ drate, scab formation that forces deep migration of epithelial cells may result in a longitudinal groove formed along the suture line. Such an effect may per­ sist for several months before reconstitution of even epidermal thickness occurs. Covering of such wounds with semi-permeable adhesive tape after suturing maintains sufficient hydration of the suture line during the period of epithelization and results in more superfi­ cial and rapid migration of epithelial cells. The result­ ing scar tends to be less indented and is more cosmeti­ cally acceptable immediately. Suture material may give rise to undesirable tissue reactions and, if severe, such reactions may retard epithelization. Ordman and Gillman6 obtained good coaptation and closure of incised wounds with a por­ ous, rayon-fiber tape (Micropore®). In this material there are minute pore-like spaces within the weave of the material. The degree of occlusion from it probably lies between that of polyethylene film and the perfo­ rated, plastic dressing investigated by Winter. Closure of superficial wounds by tapes has an advantage over closure by sutures, in that there is no reaction from imbedded material and therefore no impedence to heal­ ing on that account. Numerous tapes designed for clo­ sure of wounds have become commercially available. Obviously, they are not suitable for large, deep inci­ sions across which tendency to dehiscence may be great. Tapes are, however, useful for closure of small incisions of the type commonly employed in minor surgical procedures on the skin. It would appear from the foregoing, that a semi­ permeable type of covering is the best choice for wound dressings, especially on wounds that are left to

478

J. Dermatol. Surg. Oncol. 5:6 June 1979

heal by granulation and epithelization. We have found application of tincture of benzoin at wound edges help­ ful in providing additional adherence of adhesive tapes, like the Micropore type, which have a tendency to separate from the skin, particularly if the skin is oily or sweaty. The use of a gauze overdressing is useful on excessively exudative lesions. THE ROLE OF TEMPERATURE

Environmental temperature around wounds may also play a role in healing. It has been demonstrated that hypothermia reduces tensile strength of wounds in­ flicted immediately after induction of hypothermia up to the fifth postoperative day.7 The reason for this ef­ fect is unsure, but may relate to altered hemodynamics and sludging of blood. In another study, Lundgren et al.8 found decreased rate of healing in ordinarily wounded rabbits maintained in a cold environment, but that the rate of healing was normal in rabbits if their wounds were denervated. Those investigators theorized that denervation may abolish the neurally mediated vasoconstrictive effect of the cold environ­ ment. Filston and Vennes9 in a similar study confirmed the decreased rate of healing in wounded rabbits main­ tained in cold environments and showed that even in­ termittent exposure to cold significantly slowed heal­ ing. The same authors performed a tensometric study of full-thickness abdominal wounds in rabbits main­ tained at various temperatures and found no significant difference in the tensile strength ten days postopera­ tively in these deeper wounds. Thus, it would appear that decreased environmental temperature significantly slows healing of superficial cutaneous wounds but not of deep wounds. However, lowering the temperature of the entire body by the induction of hypothermia causes decreased tensile strength, even in deep wounds.

POLLACK

A practical application of principles is advice to pa­ tients to avoid occupational or recreational exposures to lower environmental temperatures in the immediate postoperative period following significant der­ matologie surgery. THE ROLE OF WOUND INFECTION

Bacterial contamination of surgical wounds is a com­ mon event. It becomes significant only when the num­ ber of organisms exceeds the ability of local defense mechanisms to handle them. It appears that a burden of 105 organisms per gram of tissue represents a critical level for wound infection.10 In one study,11 all patients in whom infections developed following closure had demonstrated more than 105 bacteria per gram of wound tissue at the time of closure. Similarly, it has been demonstrated that a level of bacterial growth of 105 or greater per gram of tissue interferes with suc­ cessful take of skin grafts.12 Contaminated wounds may become pyogenic wounds when there is a large amount of necrotic tis­ sue, when certain types of foreign bodies are in a wound or in its vicinity, or when local tissue defenses are diminished, as occurs in burns or in patients receiv­ ing immunosuppressive drugs.13 In the absence of these factors, local humoral and cellular defense mechanisms are usually adequate to dispose of con­ taminating microorganisms. Bacterial inflammation may have an inhibitory effect on wound healing. Burke et al.14 stress the fact that bacterial contamination, in addition to frank invasive infection, may alter wound healing, possibly by the generation of bacterial metabolic products and the tis­ sue responses they elicit. By using frequently changed split-thickness xenografts as biological dressings, these investigators were able to minimize surface contami­ nation in experimental full-thickness wounds in guinea pigs. Control animals, in whom standard dry gauze dressings were employed, were found to be more heav­ ily contaminated with bacteria and healed more slowly, more erratically and with excessive scar for­ mation. The work of Bierens de Haan et al.15, however, suggested that the mere presence of bacteria in a wound does not necessarily affect the early stages of wound healing. These investigators found that me­ chanical strength in healing wounds was not weakened by infections with Pseudomonas aeruginosa. The stud­ ies of Burke et al.14 indicated that invasive bacterial infections elicit cell-mediated immune responses in the host that account for tissue damage above and beyond that caused by direct bacterial action. Bacterial infection may be prevented by thorough debridement of open wounds, by using electrocautery sparingly, by obtaining meticulous hemostasis, by eliminating dead spaces with multilevel closures, and

by using drains in particularly deep or large excisions. The decision as to whether or not to use antibiotics is a matter of judgment and depends on the nature, size, and location of the wound. In uncontrolled clinical observations, we have found the use of topical antibiotic ointments useful in the treatment of open granulating wounds subsequent to practice of the fresh-tissue technique of Mohs. It is possible that the ointment base alone, which provides some degree of occlusion, is as helpful to healing wounds as is the antibiotic ingredient. Some controlled studies by various groups have shown lower rates of infection when topical antimicrobials are used prophylactically for controlling septic complications of venous cutdowns,16 sutured surgical wounds,1718 and open, granulating wounds.19 Other studies have failed to demonstrate significant decreases in rate of infection when topical antibiotics were used in surgical wounds.20 When a serious risk of infection is present, systemic administration is more likely to provide reliable tissue levels of antimicrobial drugs. If antibiotics are to be used prophylactically, they should be given within three or four hours of wounding in order to be effec­ tive, as bacterial contamination has usually begun by this time.21 THE ROLE OF OXYGEN TENSION

Reports by a number of investigators have shown that healing of various types of wounds is enhanced by increased local oxygen tension, and that a reduction in available oxygen inhibits repair.22-25 In a study of the healing of open wounds in domestic pigs, Winter3 found that wounds covered with oxygen-permeable polyethylene film epithelized more rapidly than did those covered with an oxygen-impermeable polyester membrane. Thus, it would seem that although most of tissue oxygen involved in the healing of wounds is likely derived from the local circulating blood, at least a portion of it may come from the environment at the wound surface. Accelerated epithelization of open wounds under hyperbaric oxygenation has also been reported26,27 and skin wounds in dogs have been found to close more rapidly at sea level than at an altitude of 3000 meters28. It is thus apparent that oxygen tension plays an important role in wound healing. A number of studies have indicated that the benefi­ cial effect of hyperoxia on the closure rate of open wounds is due to enhanced epithelization rather than to changes in the rate of wound contraction, which is unaffected by varying oxygen tensions. Medawar29 was the first to demonstrate that cultured epithelial cells survive under strictly anaerobic conditions for at least a week, but that they required oxygen in order to move and divide. J. Dermatol. Surg. Oncol. 5:6 June 1979

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WOUND HEALING: A REVIEW

The availability of molecular oxygen is also impor­ tant in collagen synthesis, in which it is required for the formation of hydroxyprolyl and hydroxylysyl residues. Uitto and Prockop30 showed that temporary anoxia may result in the formation of underhydroxylated collagen fibers of low mechanical strength. Furthermore, Kao et al.31 found that in vitro synthesis of collagen by connective tissue was acceler­ ated with increasing ambient concentrations of oxy­ gen. Another group demonstrated that maturation and cross-linking of collagen in slices of skin of chick em­ bryos increased at a linear rate when the oxygen con­ centration in incubators was raised from 20 to 95 volumes per cent.32 This finding might explain the gain in tensile strength of primarily closed wounds sub­ jected to hyperoxia. It is well known that wounds in ischemic tissues become infected more readily and frequently than wounds in well-vascularized tissues. Hunt et al.33 were able to show that the frequency of such infections can be diminished by increasing supplies of oxygen. The studies of Hohn and Hunt34 suggest that local hypoxia may interfere with the leukocyte oxidase system which is responsible for the generation of H20 2 and superoxide radical (0 2- ), necessary requisites for the killing of many species of microorganisms. In addition, it is possible that bacteria, fibroblasts, and phagocytes compete for the available oxygen within wounded tis­ sues. Infection may then result when the number of bacteria becomes sufficient to diminish the oxygen supply to the point that intracellular killing of them is insufficient to prevent its occurrence. The most important application of this information for the clinician may relate to the use of dressings that are semi-permeable, and thus allow for local gas ex­ change at the wound surface. The use of increased concentrations of locally delivered oxygen and the use of hyperbaric hyperoxia are maneuvers which may prove useful in chronically nonhealing wounds or ul­ cers, particularly when an element of ischemia is present.

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REFERENCES Pollack, S. V. Wound healing: a review. I. The biology of wound healing. J. Dermatol. Surg. Oncol. 5:389-393, 1979. Hinman, C. D., and Maibach, H. I. Effect of air exposure and occlusion on experimental human skin wounds. Nature 200:377, 1963. Winter, G. D. Epidermal regeneration studied in the domestic pig. In: Maibach, H. I., and Rovee, D. T., eds. Epidermal Wound Healing. Chicago, Year Book Medical Publishers, 1972, pp. 71-112. Winter, G. D. A note on wound healing under dressings with special reference to perforated film dressings. J. Invest. Der­ matol. 45:299, 1965. J. Dermatol. Surg. Oncol. 5:6 June 1979

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Fisher, L. B., and Maibach, H. I. The effect of occlusive and semi-permeable dressings on the cell kinetics of normal and wounded human epidermis. In: Maibach, H. I., and Rovee, D. T., eds. Epidermal Wound Healing. Chicago, Year Book Medical Publishers, 1972, pp. 113-122. Ordman, L. J., and Gillman, T. Studies in the healing of cutaneous wounds. III. A critical comparison in the pig of heal­ ing of surgical incisions closed with sutures or adhesive tape based on tensile strength and clinical histological criteria. Arch. Surg. 93:911, 1966. Lofstrom, B., and Zederfeldt, B. Effects of induced hypother­ mia on wound healing. A study in the rabbit. Acta Chir. Scand. 112:152, 1957. Lundgren, C., Muren, A., and Zederfeldt, B. Effect of cold vasoconstriction on wound healing in the rabbit. Acta Chir. Scand. 118:1, 1959. Filston, H. C., and Vennes, G. J. Temperature as a factor in wound healing. Surg. Gynecol. Obstet. 126:572, 1968. Krizek, T. J., and Robson, M. C. Evolution of quantitative bacteriology in wound management. Am. J. Surg. 130:579, 1975. Robson, M. C., Duke, W. F., and Krizek, T. J. Rapid bacterial screening in the treatment of civilian wounds. J. Surg. Res. 14:426, 1973. Krizek, T. J., Robson, M. C., and Kho, E. Bacterial growth and skin graft survival. Surg. Forum 18:518, 1967. Peacock, E. E., and Van Winkle, W. The biochemistry and the environment of wounds and their relation to wound strength. In: Wound Repair. Philadelphia, W.B. Saunders, 1976. Burke, J. F., Morris, P. J., and Bondoc, C. C. The effect of bacterial inflammation on wound healing. In: Dunphy, J. E., and Van Winkle, W. Repair and Regeneration. New York, McGraw-Hill, 1969, pp. 19-30. Bierens de Haan, B., Ellis, H., and Willis, M. The role of infection in wound healing. Surg. Gynecol. Obstet. 138:693, 1974. Moran, J. M., Atwood, R. P., and Rowe, M. J. A clinical and bactériologie study of infections associated with venous cutdowns. N. Engl. J. Med. 272:554, 1965. Fielding, G., et al. Prophylactic topical use of antibiotics in surgical wounds. Med. J. Aust. 2:159, 1965. Purssey, B. S. The use of an aerosol antibiotic in minor sur­ gery. Med. J. Aust. 1:989, 1970. Mack, R. M., and Cantrell, J. R. Quantitative studies of the bacterial flora of open skin wounds: the effect of topical antibi­ otics. Ann. Surg. 166:886, 1967. Jackson, D. W., Pollock, A. V., and Tindal, D. S. The effect of an antibiotic spray in the prevention of wound infection. Br. J. Surg. 58:565, 1971. Burke, J. F. The effective period of preventive antibiotic action on experimental incisions and dermal lesions. Surgery 50:161, 1961. Pai, M. P., Hunt, T. K. Effect of varying oxygen tensions on healing of open wounds. Surg. Gynecol. Obstet. 135:756, 1972. Lundgren, C. E. J., and Zederfeldt, B. Influence of low oxygen pressure on wound healing. Acta Chir. Scand. 135:555, 1969. Apesos, J., Hamilton, R. W., and Korostofif, E. Tensile strength in ischemic wounds in rats. Surg. Forum 19:505, 1968. Silver, I. A. Oxygen tension and epithelialization. In: Maibach, H. I., and Rovee, D. T., eds. Epidermal Wound Healing. Chicago, Year Book Medical Publishers, 1972, pp. 291-305. Fischer, B. H. Topical hyperbaric oxygen treatment of pressure sores and skin ulcers. Lancet 2:405, 1969. Shulman, A. G., and Krohn, H. L. Influence of hyperbaric oxygen and multiple skin allografts on the healing of skin wounds. Surgery 62:1051, 1967.

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Utkina, O. T. Regeneration of the skin epithelium in healing wounds under normal conditions and at reduced barometric pressure. Biol. Abstr. 45:6289, 1964. Medawar, P. B. The behaviour of mammalian skin epithelium under strictly anaerobic conditions. Q. J. Microsc. Sci. 88:27, 1947. Uitto, J., and Prockop, D. J. Synthesis and secretion of un­ derhydroxy lated procollagen at various temperatures by cells subject to temporary anoxia. Biochem. Biophys. Res. Commun. 60:414, 1974. Kao, K-Y, Hitt, W. E., Dawson, R. L., and McGavack, T. H. Connective tissue. VIII. Factors effecting collagen synthesis

by sponge biopsy connective tissue. Proc. Soc. Exp. Biol. Med. 113:762, 1963. 32. Chvapil, M. Hurych, J., and Ehrlichovâ, E. The influence of various oxygen tensions upon proline hydroxylation and the metabolism of collagenous and non-collagenous proteins in skin slices. Z. Physiol. Chem. 349:211, 1968. 33. Hunt, T. K., Linsey, M., Grislis, G., et al. The effect of differ­ ing ambient oxygen tension on wound infection. Ann. Surg. 181:35, 1975. 34. Hohn, D. C., and Hunt, T. K. Oxidative metabolism and mic­ robicidal activity of rabbit phagocytes: cells from wounds and from peripheral blood. Surg. Forum 26:85, 1975.

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Wound healing: a review. II. Environmental factors affecting wound healing.

Wound Healing: A Review II. Environmental Factors Affecting Wound Healing SHELDON V. POLLACK, M.D. A variety of factors, both intrinsic and extrinsic...
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