Wound Healing and Repair 

Wound healing is a complex and dynamic process of restoring cellular structures and tissue layers. The human adult wound healing process can be divided into 3 distinct phases: the inflammatory phase, the proliferative phase, and the remodeling phase. Within these 3 broad phases is a complex and coordinated series of events that includes chemotaxis, phagocytosis, neocollagenesis, collagen degradation, and collagen remodeling. In addition, angiogenesis, epithelization, and the production of new glycosaminoglycans (GAGs) and proteoglycans are vital to the wound healing milieu. The culmination of these biological processes results in the replacement of normal skin structures with fibroblastic mediated scar tissue. For more information on wound healing, visit Medscape’s Wound Management Resource Center.

Image of a long-standing hypotrophic scar is seen below.

This process can go awry and produce an exuberance of fibroblastic proliferation with a resultant hypertrophic scar, which by definition is confined to the wound site. Further exuberance can result in keloid formation (see image below), where scar production extends beyond the area of the original insult. Conversely, insufficient healing can result in atrophic scar formation.

Although various categories of wound healing have been described, the ultimate outcome of any healing process is repair of a tissue defect.

Primary healing, delayed primary healing, and healing by secondary intention are the 3 main categories of wound healing. Even though different categories exist, the interactions of cellular and extracellular constituents are similar.

A fourth category is healing that transpires with wounds that are only partial skin thickness.^[1]

Category 1

Primary wound healing or healing by first intention occurs within hours of repairing a full-thickness surgical incision. This surgical insult results in the mortality of a minimal number of cellular constituents.

Category 2

If the wound edges are not reapproximated immediately, delayed primary wound healing transpires. This type of healing may be desired in the case of contaminated wounds. By the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring. Foreign materials are walled off by macrophages that may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas. Usually the wound is closed surgically at this juncture, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting in prominent scarring.

Category 3

A third type of healing is known as secondary healing or healing by secondary intention. In this type of healing, a full-thickness wound is allowed to close and heal. Secondary healing results in an inflammatory response that is more intense than with primary wound healing. In addition, a larger quantity of granulomatous tissue is fabricated because of the need for wound closure. Secondary healing results in pronounced contraction of wounds. Fibroblastic differentiation into myofibroblasts, which resemble contractile smooth muscle, is believed to contribute to wound contraction. These myofibroblasts are maximally present in the wound from the 10th-21st days.

Category 4

Epithelization is the process by which epithelial cells migrate and replicate via mitosis and traverse the wound. This occurs as part of the phases of wound healing, which are discussed in Sequence of Events in Wound Healing. In wounds that are partial thickness, involving only the epidermis and superficial dermis, epithelization is the predominant method by which healing occurs. Wound contracture is not a common component of this process if only the epidermis or epidermis and superficial dermis are involved.

The amalgam of coordinated events that constitute the process of wound healing is quite complex. The steps in the procession of wound healing include inflammation, the fibroblastic phase, scar maturation, and wound contracture.^{[2, 3]} Wound contracture is a process that occurs throughout the healing process, commencing in the fibroblastic stage.^[2]

The inflammatory phase occurs immediately following the injury and lasts approximately 6 days. The fibroblastic phase occurs at the termination of the inflammatory phase and can last up to 4 weeks. Scar maturation begins at the fourth week and can last for years.^[2]

An analogous system depicts the 4 phases as hemostasis, inflammation, granulation, and remodeling in a continuous symbiotic process.^[4] This is the phase system used in this text.

Following tissue injury via an incision, the initial response is usually bleeding. The cascade of vasoconstriction and coagulation commences with clotted blood immediately impregnating the wound, leading to hemostasis, and with dehydration, a scab forms. An influx of inflammatory cells follows, with the release of cellular substances and mediators. Angiogenesis and re-epithelization occur and the deposition of new cellular and extracellular components ensues.

Initial phase - Hemostasis

Following vasoconstriction, platelets adhere to damaged endothelium and discharge adenosine diphosphate (ADP), promoting thrombocyte clumping, which dams the wound. The inflammatory phase is initiated by the release of numerous cytokines by platelets. Alpha granules liberate platelet-derived growth factor (PDGF), platelet factor IV, and transforming growth factor beta (TGF-b), while vasoactive amines such as histamine and serotonin are released from dense bodies found in thrombocytes. PDGF is chemotactic for fibroblasts and, along with TGF-b, is a potent modulator of fibroblastic mitosis, leading to prolific collagen fibril construction in later phases. Fibrinogen is cleaved into fibrin and the framework for completion of the coagulation process is formed. Fibrin provides the structural support for cellular constituents of inflammation. This process starts immediately after the insult and may continue for a few days.

Second phase - Inflammation

Within the first 6-8 hours, the next phase of the healing process is underway, with polymorphonuclear leukocytes (PMNs) engorging the wound. TGF-b facilitates PMN migration from surrounding blood vessels where they extrude themselves from these vessels. These cells "cleanse" the wound, clearing it of debris. The PMNs attain their maximal numbers in 24-48 hours and commence their departure by hour 72. Other chemotactic agents are released, including fibroblastic growth factor (FGF), transforming growth factors (TGF-b and TGF-a), PDGF, and plasma-activated complements C3a and C5a (anaphylactic toxins). They are sequestered by macrophages or interred within the scab or eschar.^[5]

As the process continues, monocytes also exude from the vessels. These are termed macrophages. The macrophages continue the cleansing process and manufacture various growth factors during days 3-4. The macrophages orchestrate the multiplication of endothelial cells with the sprouting of new blood vessels, the duplication of smooth muscle cells, and the creation of the milieu created by the fibroblast. Many factors influencing the wound healing process are secreted by macrophages. These include TGFs, cytokines and interleukin-1 (IL-1), tumor necrosis factor (TNF), and PDGF.

Third phase - Granulation

This phase consists of different subphases. These subphases do not happen in discrete time frames but constitute an overall and ongoing process. The subphases are "fibroplasia, matrix deposition, angiogenesis and re-epithelialization".^[4]

In days 5-7, fibroblasts have migrated into the wound, laying down new collagen of the subtypes I and III. Early in normal wound healing, type III collagen predominates but is later replaced by type I collagen.

Tropocollagen is the precursor of all collagen types and is transformed within the cell's rough endoplasmic reticulum, where proline and lysine are hydroxylated. Disulfide bonds are established, allowing 3 tropocollagen strands to form a triple left-handed triple helix, termed procollagen. As the procollagen is secreted into the extracellular space, peptidases in the cell wall cleave terminal peptide chains, creating true collagen fibrils.

The wound is suffused with GAGs and fibronectin produced by fibroblasts. These GAGs include heparan sulfate, hyaluronic acid, chondroitin sulfate, and keratan sulfate. Proteoglycans are GAGs that are bonded covalently to a protein core and contribute to matrix deposition.

Angiogenesis is the product of parent vessel offshoots. The formation of new vasculature requires extracellular matrix and basement membrane degradation followed by migration, mitosis, and maturation of endothelial cells. Basic FGF and vascular endothelial growth factor are believed to modulate angiogenesis.

Re-epithelization occurs with the migration of cells from the periphery of the wound and adnexal structures. This process commences with the spreading of cells within 24 hours. Division of peripheral cells occurs in hours 48-72, resulting in a thin epithelial cell layer, which bridges the wound. Epidermal growth factors are believed to play a key role in this aspect of wound healing.

This succession of subphases can last up to 4 weeks in the clean and uncontaminated wound.

Fourth phase - Remodeling

After the third week, the wound undergoes constant alterations, known as remodeling, which can last for years after the initial injury occurred. Collagen is degraded and deposited in an equilibrium-producing fashion, resulting in no change in the amount of collagen present in the wound. The collagen deposition in normal wound healing reaches a peak by the third week after the wound is created. Contraction of the wound is an ongoing process resulting in part from the proliferation of the specialized fibroblasts termed myofibroblasts, which resemble contractile smooth muscle cells. Wound contraction occurs to a greater extent with secondary healing than with primary healing. Maximal tensile strength of the wound is achieved by the 12th week, and the ultimate resultant scar has only 80% of the tensile strength of the original skin that it has replaced.

The process of wound healing constitutes an array of interrelated and concomitant events.Understanding of these processes and effectors on these processes contiue to expand.

Future advances in wound healing will focus on affecting the agents that influence the processes involved in the repair of damaged tissue. Laser techniques, nonlaser techniques, and other modalities are being explored to enhance the proliferation of cells, the migration of cells, and the acceleration of the healing of wounds.^{[6, 7]}

Human cell–conditioned media developed in embryologiclike conditions has been shown to improve healing times in postlaser facial skin.^[8] Fetal tissue can heal scarless due to the unique characteristics of fetal epithelial and mesenchymal cells and the functioning of the fetal immune system.^[9] Hyperbaric oxygen has also been used to promote healing.^[10] Stem cells, in particular adipose-derived stem cells, have been shown to ameliorate wound healing, and continued research in these areas appears promising.^{[11, 12]}