Pathophysiology of the Burn Scar

Prehistoric and Historic Perspectives

Wounds due to combat, hunting injuries, accidents, and thermal injuries have been the leading causes of death in humans for millennia, whereas prolonged survival of large full-thickness wounds is a recent phenomenon. Complex biological responses to cutaneous injury have evolved over time without evolutionary pressure to evolve appropriate healing responses to large wounds. There are records of human attempts to improve wound healing in ancient texts from Mesopotamia and Egypt. Guido Majno has explored what can be learned from archeology and paleontology regarding wounds and their treatment in ancient times and provides an accurate description of the wound healing process in lay terms. In the development of modern medicine, the advances in wound treatment advocated by Ambroise Pare (1520–1590) stand out, together with the antisepsis campaign of Joseph Lister (1827–1912) and the development of antibiotics and other modern methods of treatment described in this book.

Incisional Wounds With Primary Closure

The essential components of wound healing are easily understood. They are: (1) activation of tissue repair in the wound by fibroblasts and small blood vessels and an inflammatory response initiated by vascular leakage and (2) entry into the wound of circulating polymorphonuclear neutrophils, lymphocytes, and macrophages. When a sharp incision is closed while still sterile, minimal vascular leakage and inflammation occur, and the predominant reaction to injury occurs in the fibroblasts present in the dermis and subcutaneous tissue. These resting connective tissue cells are rapidly activated to secrete collagen, which quickly bridges the small remaining gap to restore the resistance of the skin to tearing. Vascular continuity is restored by budding and remodeling of blood vessels, and the basal keratinocytes of the epidermis divide briefly to restore the complete structure of the epidermal barrier. All that remains to indicate the site of injury is a linear ribbon of dense collagen with little flexibility that marks the site of the incision, as well as small scars that mark the suture sites. This process of incisional wound healing was well described in humans by Ross and colleagues.

Delayed Wound Closure “by Second Intention” and Wound Contraction

If the epidermis and dermis are incised or removed and the edges of the wound remain separated, then the resultant inflammatory and reparative events are prolonged and more prominent. Extensive leakage of blood plasma by damaged small blood vessels maintains an outward flow that serves to keep the wound clean but causes deposition of coagulated fibrin and other desiccated proteins on the wound surface. Conversion of fibrinogen into fibrin fills the gap in the epidermis and provides a gelatinous matrix capable of sustaining migrating cells. Thrombin stimulates expression of interleukin-6 (IL-6) in connective tissue cells. Degranulation of platelets releases platelet-derived growth factor (PDGF) and other proinflammatory cytokines. Fibrin degradation releases peptides that stimulate fibroblast proliferation and secretion, division of vascular endothelial cells, and production of cytokines by other cells. Dermal fibroblasts, together with circulating stem cells, divide rapidly in the wound bed and secrete large quantities of collagen and proteoglycans, with predominance of type III collagen. Simultaneously the endothelial cells of small blood vessels proliferate rapidly and form numerous small capillary loops that extend upward toward the surface. Together these cells form a mass of granulation tissue that covers the wound. These activities of fibroblasts and endothelial cells are stimulated by cytokines and other peptides, largely secreted by monocytes and lymphoid cells that infiltrate the wound bed. Certain proteins and peptides that are normally present in blood plasma also stimulate and enable formation of the wound matrix, notably fibronectin and vitronectin. Polymorphonuclear neutrophils also enter the wound bed in large numbers where they phagocytize and kill bacteria and fungi that gained entry to the dermis and subcutis through the open wound. Next the fibroblasts develop interconnections among themselves and produce and assemble the contractile machinery of actin and myosin within the cytoplasm of each cell. These interconnected myofibroblasts contract to shrink the size of the open wound, pulling adjacent intact skin to cover the wound bed. Wound contraction is most dramatic in experimental wounds of rodents; however the effects of wound contracture in applying tension to surrounding tissues can be seen in humans as well. Simultaneously with these processes, the basal keratinocytes of the cut edges of the epidermis proliferate and change to a migratory and secretory phenotype and begin to invade the wound bed between the granulation tissue layer and the scab of dried proteins on the surface. Once they make contact to seal the center of the wound, the migrating keratinocytes change phenotype again and restore the normal laminated structure of the epidermis and produce a new basal lamina. Melanocytes also migrate during healing of large wounds and establish a degree of pigmentation in the healed wound that approximates the pigmentation of the uninjured skin. It should be noted that only the epidermis regenerates to resemble the normal epidermis. Hair follicles, sweat glands, and other epidermal appendages do not regenerate. Thus the part of the wound that was not closed by contracture remains dry, hairless, and flat. Furthermore the restored dermis in a fully healed scar is composed of collagen type I fibers running in straight lines adjacent to one another and parallel to the surface, providing strength (though somewhat less than the native skin) but far less elasticity and flexibility than the connective tissue of the normal dermis.

First-Degree or Superficial Injury of Skin

Superficial burn wounds are those in which part or all of the epidermis is lost, but the epidermal basal lamina remains intact and the dermis is uninjured. In these areas, only epidermal regeneration is required, hair follicles and sweat glands remain intact, and healing can occur with little or no disfigurement.

Second-Degree or Partial-Thickness Injury

In partial-thickness wounds, the entire epidermis and the upper part of the dermis become necrotic. If left intact, the presence of a large quantity of devitalized tissue requires prolonged activity of macrophages to clear the necrotic debris. Granulation tissue forms underneath the necrotic dermal tissue, and epidermal migration occurs under the eschar formed by dead tissue, leading to restoration of the epidermis and production of dermal connective tissue in the form of a thin scar. The deep portions of the hair follicles remain viable, and the keratinocytes lining the hair follicles become migratory and undergo mitosis behind the migrating cells, eventually covering the surface with new epidermis derived from the hair follicle. In severe cases, loss of hair follicles may lead to insufficient regenerative activity to cover the surface. Multipotent stem cells within the hair follicles generate cells that can multiply, migrate, and regenerate the surface epidermis. The stem cell population that was first identified is slowly cycling, expresses the conventional stem cell surface marker CD34, and resides in the bulge region of the follicle near the attachment of the arrector pili muscle. More recently, additional stem cell populations have been identified that reside in the isthmus region and the hair germ region of the follicle and express distinct markers. Much is being learned about the function of these stem cells by studying knockout and overexpressing mice. The changes in follicular stem cells during healing of burn wounds, however, remain to be described.

One new aspect of hair follicle biology that is of great interest for burn surgeons is the delineation of the role of the dermal papilla, the tiny cluster of mesenchymal cells within the hair bulb. Fetal development of hair follicles depends on interaction between epithelial cells of the epidermis and mesenchymal cells. The mesenchymal cells of the dermal papilla, which can be amplified in culture using keratinocyte-conditioned medium, can induce formation of hair follicles from interfollicular skin. Formation of new hair follicles, complete with hair, has been induced in hairless nipple skin of the mouse and in the renal capsule. Since one of the major problems in long-term care of burn patients is alopecia, the possibility that hair follicles could be induced to regenerate is very appealing.

Third-Degree or Full-Thickness Injury

In full-thickness burns, thermal injury extends deep enough to destroy all of the hair follicles that have the capacity to regenerate the epidermis and some of the upper subcutaneous tissue may also become necrotic. In this case regeneration of the epidermis from hair follicles is not possible, and the wound can develop an epidermal covering only slowly as the epidermis lateral to the wound spreads out over the entire wound surface. During this time, the necrotic tissue in the wound bed is at risk of infection, and extensive activity of tissue macrophages is required to eventually remove it.

Changes in Vascular Permeability

In order to review current understanding of the processes important in wound healing, each will be considered separately. Changes in local blood vessels are the earliest component of the wound's response to injury and are essential for the succeeding steps. Plasma exudation is due to increased permeability of venules to proteins, largely due to local release of histamine and vascular endothelial growth factor (VEGF) from mast cells and substance P from local sensory nerve endings. With burn injury, there is an added component of plasma leakage that occurs for several hours throughout the body in response to unknown stimuli. Of course, both plasma and red blood cells enter the wound through broken or necrotic blood vessels. Infection triggers further plasma exudation by constantly stimulating and prolonging the vascular phase of acute inflammation. Additionally the newly formed capillaries of granulation tissue allow passage of plasma proteins and fluid until they mature. Certain plasma proteins, notably fibronectin and vitronectin, are important in stimulating reparative responses in the wound.