The inflammatory phase of healing is the initial response to any injury involving more than an epithelial surface. This phase can be divided into two separate but simultaneously occurring responses: a vascular and a cellular response. Both are initiated by amines, most notably histamine, as well as the kinins and proteolytic enzymes released by the injured tissue. Immediately after injury, a transient vasoconstriction of the local vasculature lasts for 5 to 10 minutes. Vasoconstriction is followed by vasodilatation and an increase in vascular permeability. Edema caused by the escape of plasma through altered vessel walls becomes clinically apparent at this point.

The cellular response is characterized by the migration of leukocytes into the injured area. Although the agents responsible for this active migration of leukocytes remain unclear, chemotactic factors are thought to play a major role. Initially, the polymorphonuclear leukocytes and monocytes in the wound are present in the same concentration as in the systemic circulation. As a result, polymorphonuclear leukocytes predominate for the first 3 days. Because polymorphonuclear leukocytes are relatively short-lived compared with monocytes, the latter stages of the inflammatory phase are characterized by a predominance of monocytes that transform into macrophages. These leukocytes actively phagocytize bacteria, foreign proteins, and necrotic debris. As polymorphonuclear leukocytes die, their intracellular enzymes and debris are released into the wound and become part of the wound exudate. These released enzymes also facilitate the breakdown of material not phagocytized by the leukocytes. This accumulated exudate or pus develops even in the absence of bacteria. Even when this exudate is sterile, the presence of proteolytic enzymes, including collagenase, can interfere with epithelialization and fibroplasia and, thus, interfere with continued wound healing. Poor wound healing, however, is more common in wounds contaminated with bacteria and foreign material. In these cases, the inflammatory response may persist for long periods of time.

By virtue of their exposed location, the epithelial surfaces of the gastrointestinal, urogenital, and respiratory tract as well as the skin itself are continually subjected to the physical and chemical trauma associated with the activities of daily living. As a result, these surfaces are constantly replacing damaged or destroyed cells through a process known as epithelialization. Epithelialization occurs by migration and subsequent maturation of immature epithelial cells from the deeper basal layers of surrounding areas. If the cellular damage is confined entirely to the epithelium, the healing response is merely an exaggerated form of the basic normal replacement process.

If an injury involves the supporting connective tissue beneath the epithelium, however, the other components of the healing processes, in addition to epithelialization, become involved. If the injury severs blood vessels, the vessels retract, and the process of hemostasis is initiated. If bleeding is not too severe, a blood clot soon forms. This clot subsequently contracts, dehydrates, and becomes a scab. Within 12 hours, basal cells from the surrounding epithelial surfaces begin migrating onto the injured surface. Epithelial cells move beneath the scab, detaching it from the wound and sealing the surface. In incised and sutured wounds, epithelialization generally produces a watertight seal within 24 hours of injury. This new layer of epithelial cells is initially thin and poorly attached to the underlying surface, rendering it susceptible to injury from even minor trauma. Final epithelial healing is accomplished by differentiation and maturation of the migrated cells and by scar formation through fibroplasia.

The process by which wounds regain strength is termed fibro-plasia. Fibroplasia results in the production of the collagen necessary to form a fibrous scar and ultimately determines the final strength of the healed wound. This process begins with the differentiation of mesenchymal cells into fibroblasts. Fibroblasts then migrate into the wound, apparently along fibrin strands produced during clot formation. Once at the injury site, fibroblasts proliferate and manufacture the glycoproteins and mucopolysaccharides that make up the ground substance of connective tissue. Ground substance is an amorphous matrix that is believed to induce aggregation of collagen subunits and influences the final orientation of the fibers.

Once the ground substance is produced, fibroblasts begin to synthesize the basic building block of collagen-tropocollagen. Tropocollagen is a stiff elongated macromolecule of three helically intertwined chains of amino acids consisting of two identical α1 chains and one α2 chain. Within the ground substance and at the proper pH, osmolality, and temperature, tropocollagen molecules polymerize into collagen fibrils by forming covalent bonds with their neighbor. These fibrils bond with other fibrils to form collagen bundles. It is not until 4 to 5 days after injury that the wound produces enough collagen to result in a measurable increase in wound tensile strength. Before this time, the wound is held together only by fibrous adhesion. This time frame between wounding and an increase in tensile strength originally was referred to by Howes and Harvey as the “lag period” of wound healing.

The manner in which tissue heals is dependent on whether tissue integrity is simply interrupted (as in a surgical incision) or tissue is removed (as in an avulsion injury). In both types of injury, tissue seals itself, begins to reepithelialize, and synthesizes collagen for structural support. However, when large amounts of tissue are missing, the edges of the wound must be brought closer together so that the previously noted tissue responses can repair the defect. This process is known as contraction. Contraction of wound margins begins about 5 days after injury and corresponds with the fibroplasia phase of healing. Because this process can be inhibited by cytochrome poisons, such as potassium cyanide, and by smooth muscle relaxants, older theories attributing wound contraction to passive collagen changes have been discarded. Instead, wound contraction appears to be an active process produced by contractile proteins within the fibroblasts. If the area is too large for contraction to bring the edges together, the wound remains covered with granulation tissue, or if small enough, it is covered with epithelium only. Epithelialization of such a wound prevents weeping, but without the normal underlying supporting stroma, it remains too fragile to provide lasting protection. Pathologic progression of skin contraction ultimately may result in restriction of joint or limb mobility. This deformity is termed contracture and should not be confused with contraction.

The bulky scar formed during the fibroplasia phase consists of randomly oriented soluble collagen fibers. This scar has little tensile strength. During scar maturation, the disordered fibers are replaced with fibers arranged in a more orderly fashion, producing a denser and stronger scar. Collagen fibers also continue to form covalent bonds within fibrils as well as between adjacent fibrils and fibers, resulting in a continued increase in wound tensile strength over time. This maturation process may continue for years.

During scar maturation and remolding, the breakdown of old disordered collagen slightly exceeds production of new organized collagen fibers. The resulting new scar is softer and less bulky than is the original scar but also is stronger because of its more organized and extensively cross-linked nature. However, if collagen production exceeds breakdown, then a keloid or hypertrophied scar results.

Healing occurs by primary intention if the wound layers are reapproximated following injury. This apposition of tissue layers allows healing to occur in a minimum of time, with no separation of wound edges and with minimum scar formation. This is the desired mode of healing for surgical incisions.

It has been known for centuries that a wound has a higher resistance to infection when left open rather than closed. This was demonstrated experimentally in dogs by Bilroth, who applied dressings soaked in liquid feces and pus to wounds. Wounds left open remained healthy in appearance, whereas those that were subsequently closed became infected. As a result, contaminated or infected surgical wounds often are left unapproximated and allowed to close spontaneously. This type of wound healing is referred to as healing by secondary intention. This healing process obviously is more complicated and prolonged than that of primary intention. The wound eventually heals by a combination of contraction and the formation of granulation tissue with the wound gradually filling in from the raw surfaces. This type of healing is slow and frequently characterized by formation of excessive scar tissue. Granulation tissue from the healing wound also may protrude above the wound margin during this process. This can prevent final epithelialization of the surface and require further treatment for complete healing.

Wound healing by third intention, also known as delayed primary closure, refers to the technique of wound closure after a period of delay. This method often is used after postoperative wound breakdown or as an alternative to healing by secondary intention of wounds that should not be closed primarily, such as grossly contaminated or infected wounds. The timing of closure is important. After delays of 7 to 8 days, the wound edges become increasingly difficult to approximate because of the increasing collagen content. Edlich and colleagues have suggested that closure on or after the 4th day appears to be ideal. This concept also is supported by Lowery and Curtis, who showed that wounds closed after a delay of between 3 and 6 days have the lowest infection rates. Furthermore, studies by Fogdestam revealed that wounds closed during this time frame also have greater wound strength at 20 days than do wounds closed primarily.

One of the oldest suture materials is plain catgut. Catgut consists of highly purified strands of collagen obtained from the submucosa of animals. Despite its name, catgut normally is obtained from sheep or cattle intestines. The name is believed to have originated from the Arabic term kitgut, which referred to the strings of a musical instrument known as a kit. Kitgut was made from sheep intestines and probably served as a readily available source of suture material. Over the years, the term has evolved into catgut.

Because plain catgut is a foreign protein, it elicits a marked inflammatory response in tissue. It is rapidly degraded by proteolytic enzymes released by white blood cells. This suture loses more than 70% of its tensile strength in 7 days and is totally digested by 70 days. Plain gut is used in tissue in which strength is needed for very short periods of time. It is ideal for Pomeroy tubal ligations because it dissolves rapidly and thus allows the severed ends to fall apart. Less rapidly absorbed sutures, particularly permanent suture, are associated with higher failure rates, probably because of fistula formation.