Symposium on Response to Infection and Injury I

Wound Healing

John A. Schilling, M.D.*

A wound may be defined as the disruption of cellular and anatomic continuity. Wound healing is the restoration of continuity. This biologic process can only be accomplished by cell regeneration, cell proliferation, and collagen production. In higher animals regeneration is limited; and epithelial, endothelial, and fibroblastic proliferation with collagen production substitutes for regeneration and occurs in an orderly and predictable sequence of events that begin at the time of wounding and continue for several months. Traditionally, the phases of wound healing have been described repeatedly as the lag phase, the logarithmic phase, and the waning phase to fit the sigmoid curve of tensile strengths or wound closures during the time course of healing in experimental animals. This classification, in the opinion of the author, has led to confusion in recognizing and understanding the many processes and cell types involved in wound healing. At least 15 cell types from the bone marrow, reticuloendothelial system, thymus, liver, and tissue cells existing in the local area of the wound, are involved in the wounding, inflammatory, proliferative, and remodeling phases of wound healing. Ordinarily these phases are physiologic; their quantitative extremes may be pathologic. Finally, it is comforting to state that most of the cellular and physiologic mechanisms involved in wound healing are the same mechanisms as those involved in our other inflammatory responses, immune responses, surveillance and detection mechanisms, infection, neoplasia, and rejection of transplanted tissues.

PHASES OF WOUND HEALING Wounding Loss OF ORGAN FUNCTION. There can be an immediate loss of all or part of the function of the organ wounded. This may bear little rela'Professor and Chairman, Department of Surgery, School of Medicine, University of Wash· ington, Seattle, Washington

Surgical Clinics of North America - Vol. 56, No.4, August 1976

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tionship to the magnitude of the wound. Immediate diagnosis and organ function support are necessary to salvage life and permit healing. Partial loss of organ function may be less obvious although quite deleterious as it may involve the lung, kidney, liver, or alimentary tract with resulting deficits. Primary or secondary organ function failure may occur any time during the convalescent phases and requires continued surveillance. Further discussion is beyond the scope of this article, but the pathophysiologic significance is mentioned first to emphasize the importance of considering the total patient and restoring normal physiologic function. SYMPATHETIC STRESS RESPONSE. The circumstances involved in the trauma of wounding, be it accidental or surgically planned, evoke a stress response that may directly or indirectly influence wound healing. For example, excessive sodium retention and edema, or excessive losses of potassium and nitrogen, can influence the local wound and the cellular responses involved in inflammation and repair. HEMORRHAGE AND BLOOD CLOTTING. Hemorrhage occurs to a greater or lesser degree in every wound and must be controlled. The pathophysiology of hemorrhagic shock and its influence on other organs can have a major effect on wound healing. Locally, hemostatic mechanisms involved in intravascular coagulation deserve emphasis, and these are extravascular tissue tension, vascular retraction and contraction, intravascular platelet aggregation, fibrin formation, and blood clotting. Effective platelet aggregation can occur with counts as low as 25,000 to 30,000 per cubic milliliter, although platelet transfusions are recommended when counts fall below 50,000 per cubic milliliter if there is continued oozing. Extravascular fibrin formation is important in providing an early inflammatory seal of the wound and in providing a lattice framework for the Inigration of endothelial and fibroblast cells and collagen. An extravascular blood clot, however, increases the magnitude and extent of dead and devitalized cells and debris that must be removed by the body's defense mechanisms, enlarges the dead space of the wound that must be obliterated, and is an excellent culture medium. Despite statements to the contrary, an extravascular blood clot is a burden for the processes of wound healing and may produce serious complications. The intravascular blood clot is the physiologically essential requirement. BACTERIAL CONTAMINATION. This occurs in almost every wound, or restated, every wound is a culture of bacteria supplying excellent nutrients on the one hand, and transporting bacterial antagonists on the other. A bacterial-host struggle occurs in every instance of wounding when the virulence of the organism is pitted against the resistance of the. host. Local factors in wounding and wound management may be critical in its outcome. The body's defense against bacteria is usually effective when the numbers of bacteria do not exceed 103 per cubic centimeter. A septic wound may contain bacteria in numbers ranging to 107 109 per cubic centimeter. The implications are obvious for the surgeon-to reduce the numbers of bacteria by sterile technique, aspiration, irrigation, debridement, and the judicious use of antibiotics just prior to and during surgery.

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CELL DEATH-FOREIGN MATERIAL CONTAMINATION. Dead and devitalized cells in variable numbers are the inevitable result of wounding and must be digested and absorbed by cellular enzymatic and lysosomal action, exteriorized by a fibroblastic-collagenic obliterative process, or calcified. The same applies to organic and inorganic debris or materials that are introduced by the wounding agents or the techniques of repair. A cubic centimeter of dead tissue will represent about 100,000,000 (lOS) cells. A cubic centimeter of blood represents about 5,000,000,000 (109 ) cells. A hundred hemostats may represent a billion (109 ) dead cells or more. These statements are made to emphasize the invariable presence of dead and devitalized cells, foreign bodies, and debris; and to emphasize the magnitude of their numbers and the importance of reducing their quantity to a tolerable minimum.

InHammatory Phase ALTERATION OF CAPILLARY PERMEABILITy-TRANSUDATION. Immediate capillary construction that aids intravascular coagulation is followed shortly by capillary dilatation and increased permeability. This leads to leaking at endothelial cell junctions with transudation of plasma proteins, antibodies, complement, water, electrolyte, plasma proteins, and all of the circulating humoral substances of the blood into the wound, including biologically active polypeptides that may playa role in chemotaxis and the enhancement of the later eInigration of white blood cells into the site of the wound. This transudation increases in magnitude for approximately 72 hours. Accompanying this transudation is an alteration in the composition of the ground substance, particularly the macromolecular glycoproteins (large protein molecules with sugar side chains) and mucopolysaccharides (large amino sugar molecules with protein side chains). This in turn alters the adjacent cell membranes, the stickiness and adhesiveness of cells, and the influence of the circulating cloud of ionized particles of the interstitial water and intracellular electrolytes that have leaked out. The intercellular spaces were formerly thought to be filled essentially by water and electrolyte and plasma proteins of small molecular size. This concept, however, has changed, and the intercellular spaces are now known to be filled with large macromolecules of great molecular weights and include the glycoproteins, mucopolysaccharides, tropocollagen, and other biocolloids. They are ionized, weak polyelectrolytes and assume three-dimensional character. Within this weakly ionized macromolecular mesh circulate the interstitial water, electrolytes, hormones, trace elements, proteins, and catecholamines of the blood plasma. Obviously, the ground substance is capable of trapping and sequestering large volumes of interstitial fluid and must influence the function of contiguous cell membranes. In this area not enough basic scientific knowledge is known as yet to contribute to better treatment, but it is an intriguing area of research. CELLULAR MIGRATION. The first inflammatory cells to appear are the white cells or polymorphonuclear granulocytes without which there can be no effective control of sepsis. Several years ago the author expressed the concept of "tissue perfusion" by white blood cells. This is still a useful concept when considering the inflammatory response, sur-

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veillance and detection mechanisms, and removal of abnormal or dead cells. This perfusion would be enhanced by chemotactic factors, alterations in cell stickiness, increase in blood flow, increase of capillary permeability, and increase in production of white cells by the bone marrow. Effective control of infection can still occur when counts drop below 1000 white cells per cubic milliliter but still above 200 to 500. This is important to evaluate when surgery is carried out during the course of cancer chemotherapy, immune suppression, or therapeutic or accidental irradiation. In an increasing number of blood banks white cells can be harvested and transfused, and though shortlived can tide a patient over a transient period of aplasia with sepsis. The next cells to appear are the lymphocytes about which there is an increasing body of knowledge concerning their sensitization to specific target cells and their production of specific antibodies. Macrophages make their appearance at this time, and their lysosomes are heavily laden with hydrolytic enzymes which are essential in the digestion and transport of cellular and organic debris from the wound site. Mast cells within the tissue also de granulate and assist in the foregoing processes. Finally, plasma cells appear with production of specific antibodies to the specific bacterial and foreign body antigens present and persisting in the wound site. There are many complement factors (Cl_C9) that playa significant but yet incompletely understood role in the killing of bacteria and abnormal or foreign cells, and the inflammatory response. They form several combinations of antigen-antibody-complement complexes, each with different acute and chronic inflammatory responses. Increased knowledge in this area may lead to better control of pathologic inflammatory responses. BACTERIAL PROLIFERATION. Finally, a multiplication of bacteria in the wound occurs early in this post-wound inflammatory process. If the foregoing mechanisms fail in the control of the numbers of bacteria, a wound infection results, usually 4 to 5 days after the wound. The exact time varies with the type and virulence of the organism and the host defense mechanisms. Examples range from a streptococcal cellulitis during the frst 48 hours to a granuloma after many weeks. Proliferative Phase Following the unknown stimulus of the breach of continuity of the wound, there is a proliferation of fibroblasts, epithelial, and endothelial cells in the local area. In a sense, the wound serves not only as a bacterial culture, but also as a tissue culture. The fluid transudate, described above, contains every element for growth. These cells multiply and migrate in a random fashion into the space or over the denuded surface created by the wound. They are guided by the fibrin strands, anatomic tissue planes, and physical tension planes in this random migration. The cells migrate at a rate of about 0.2 mm per day. In an unknown way their migration ceases when they touch a like cell (contact inhibition). This leads to a sorting out and an ultimate order in the enormous mixed cell population of the wound.

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In a relatively axiomatic statement, it can be said no wound is healed until its epithelial, endothelial, or mesothelial surfaces are covered. This is particularly true of all wounds involving the skin, gut, and hollow organs, where epithelium is essential as a bacterial barrier. The importance of approximating and early covering by grafting, flaps, and pedicles is apparent in controlling sepsis and accelerating wound healing. Heterografts can be very effective in the temporary control of sepsis. Great arteries in the neck, axilla, and groin must always be covered as their wall invariably necroses and ruptures when they are exposed in open granulation tissue. Granulation tissue is a varying admixture of capillaries from the hollowed out endothelial buds from the wound edge and fibroblasts. It is wet with transudate and laden with circulating, migrating white cells transported by the capillaries, and its primary function is to fill the space created by the wound and to create a bacterial barrier. This space is also decreased by contracture, which may be one of the functions of collagen, although the nature of the contracture process is unknown and beyond the scope of this article. Granulation tissue also serves as the bed for the advancing epithelial cells. The magnitude of the mass of granulation tissue can be reduced surgically by careful approximation and appropriate obliteration of the wound dead space. In open wounds excessive granulations should be excised. The fibroblast in granulation tissue is an active, protein-producing cell and synthesizes collagen and the mucopolysaccharides. The collagen molecule is a three-stranded helix 3000 angstra in length and made up by repeated polymerization of proline, hydroxyproline, glycine, and many other amino acid residues. Without collagen there is no strength or permanence in the healing wound. Further, collagen plays a key role in the skeletal and cellular supporting systems throughout the body. Of our total body protein mass 30 per cent is collagen. It is not inert, but is produced by fibroblasts, osteoblasts, and chondroblasts and lysed and absorbed in response to the body's functional needs. The classic statement of Dr. Dunphy is worth repeating, "the fibroblast (and its product collagen) is the ubiquitous ally of the surgeon." Obviously, an excessive, prolonged, or ectopic inflammatory process can lead to excessive pathologic collagen production and fibrosis, examples of which are well known to the surgeon-contractures, keloids, adhesions, fibrotic narrowing. Here avoidance of sepsis, approximation, grafting, and attenuating the inflammatory response can minimize these complications. Remodeling Phase The wound healing process is a complex, integrated cellular response and begins rather suddenly and extends over several months. Cell production must be balanced by cell death; collagen production must be balanced by hydrolysis, degredation, and absorption. Capillary formation must be balanced by capillary obliteration. If this does not occur, there could be a neoplastic-like, uncontrolled overproduction of cells and their products. It is beyond the scope of this article to review the large speculative literature on the nature of the stimulus and inhibition of these cellular processes. They are really unknown.

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Clinically, however, this process seems governed by function where, in an unknown way, the appropriate cells persist and unneeded collagen is lysed and removed. Collagen realigns and forms sheets or strands parallel to physiologic tension lines with increasingly firm chemical cross linking. As the capillaries obliterate, there is a softening of the wound. Remaining fat cells fill beneath grafts and in the wound areas. Basal cell activity of the epithelium diminishes. Failure to recognize the importance of function can lead to late wound complications of pain, adhesion, and contracture with failure of rehabilitation.

ACCELERATION OF WOUND HEALING The events and mechanisms of the repair process and the approximate time of their initiation and overlap have been depicted in Figure 1 and superimposed on a classic sigmoid-shaped biologic wound response curve. Following the wound, a period of intense cellular activity leads to a cellular response that controls infection and restores continuity. Ultimately, after a series of inhibitory feedback mechanisms, the response ceases, but from a practical point of view soft tissue healing levels off

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Wound healing.

Symposium on Response to Infection and Injury I Wound Healing John A. Schilling, M.D.* A wound may be defined as the disruption of cellular and ana...
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