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Wound healing encompasses a cascade of events that the body employs to resolve injury. The body’s top priorities are to stop blood loss, restore function and to prevent infection. Repairing tissue involves restoring both cells and their protein matrix. The protein matrix defines tissue structure and supports cellular adhesion and migration. Cells influence the composition and activity of the matrix, and vice versa. Generally, these events are grouped into three phases: inflammatory, proliferative/repair, and remodeling/maturation.
The Inflammatory Phase
The inflammatory phase begins at the time of injury and continues for a few days at the most. The body aims to curtail bleeding and to clean and sterilize the wound area. A temporary fibrin protein matrix aids blood clotting and provides a base for cellular infiltration. Platelets circulating in the blood attach to the fibrin matrix to further prevent excessive bleeding. Swelling is often noticed at a site of injury, caused by an influx of fluid. The fluid is calledexudate, which contains inflammatory cells and proteins. Debridement refers to the removal of debris and the cleansing of a wound by the body. The main mode of debridement is phagocytosis, or “eating” of foreign objects by inflammatory cells such as neutrophils and macrophages. Debris or bacteria are engulfed, then broken down into smaller, less harmful pieces for removal. Inflammatory cells must distinguish host cells (self) from non-self cells in order to protect the body. Bacteria, for example, contain distinctive sugars on their surfaces that inflammatory cells recognize as foreign. Inflammatory cells are also aided in their search by opsonization, a specialized adsorption of serum proteins to non-self cell surfaces that targets the non-self cells for phagocytosis.
Neutrophils are the first cells drawn to the site of injury, arriving within a few hours. They are short-lived, fast migrating phagocytic cells. They circulate in the blood until signaled by a wound. The process by which they exit the circulation, move out of blood vessels into tissue, is known as extravasation. Cellular movement toward a chemical signal, such as those from a wound, is known as chemotaxis. As neutrophils subside, they make way for macrophages. Macrophages tend to remain at a wound site for a few days to weeks and play multiple roles in inflammation and wound healing. Macrophages phagocytose (“eat”) foreign and debris material; they send chemotactic signals to other cell types that will participate in wound healing. They are one type of antigen-presenting cells. Antigen-presenting cells phagocytose and degrade infectious agents, then display fragments on their surfaces. B cells can then be produced to be reactive to those fragments, and hence, specifically recognize and destroy the infectious agent in the future. In this way, an immunity is built.
The Proliferative Phase
In the proliferative phase, the body aims to fill and close the wound area. This occurs a few days to a few weeks post-injury. The temporary fibrin matrix is replaced by a more developed tissue intermediate known as granulation tissue. Granulation tissue contains macrophages, fibroblast cells, some newly formed blood vessels, and a more complex protein matrix. Cells from the periphery of the wound multiply in order to fill the gap. Fibroblasts in the granulation tissue “pull” on the matrix, causing the wound to contract and close.
The Remodeling Phase
Finally, the remodeling phase defines the resolution of the wound. This phase can take place weeks to months after the initial injury. Maturation of the matrix and cellular content continues. In some cases, healed tissue is much like uninjured tissue, while in other cases, scar tissue remains. The reasons are not yet completely understood. Either way, the body has achieved its goal to restore function, even if the form is not perfect.
Keep in mind that the stages of wound healing are arbitrary classifications, and that the processes described above do somewhat overlap temporally. For more in-depth discussions of wound-healing events and players, please refer to the resources listed below.
The Foreign Body Reaction
The foreign body reaction begins as wound healing, including accumulation of exudate at the site of injury, infiltration of inflammatory cells to debride the area, and the formation of granulation tissue. However, the persistent presence of a biomedical implant, splinter, particulates, or other foreign bodies inhibits full healing. Rather than the resorption and reconstruction that occurs in wound healing, the foreign body reaction is characterized by the formation of foreign body giant cells, encapsulation of the foreign object, and chronic inflammation.
Foreign Body Giant Cells
Foreign body giant cells are the products of macrophage fusion, and are a hallmark of the foreign body reaction. When macrophages encounter a foreign object too large to be phagocytosed, such as an implant, it is thought that the macrophages experience “frustrated phagocytosis.” They fuse to form larger foreign body giant cells composed of up to a few dozen individual macrophages. Giant cells secrete degradative agents such as superoxides and free radicals, causing localized damage to implants and other foreign bodies. Currently, little is known of the role of foreign body giant cells. It is hard to say whether they are “more or less inflammatory” than a collection of macrophages. Macrophages and foreign body giant cells tend to remain at the surface of an implant for the duration of its residence.
Encapsulation refers to the firm, generally avascular collagen shell deposited around a foreign body, effectively isolating it from the host tissues. This response was developed as a protective measure. Encapsulation is especially problematic for devices designed to interact with the body, such as glucose sensors. The foreign body reaction can lead to chronic pain and device rejection and failure.
So why doesn’t the body heal normally around implants? This is still a heavily studied question in UWEB labs as well as many other labs. Factors that seem to influence the host response include implant location, size, shape, micromotion, surface chemistry, surface roughness, and porosity. Characteristics of the host, such as age and general health, also affect response to an implant. A greater understanding of the foreign body response and how it differs from normal wound healing may aid in design of more biocompatible materials and devices.
Dee KC, Puleo DA, Bizios R. Wound healing. In: An introduction to tissue-biomaterial interactions. Hoboken, New Jersey: John Wiley & Sons Inc.; 2002. p.165-214.
Greenhalgh DG. The role of monocytes/macrophages in wound healing. In: Robinson JP, Babcock GF, editors. Phagocyte function: A guide for research and clinical evaluation. Wiley-Liss, Inc; 1998. p. 349-357.
Anderson JM, Gristina AG, Hanson SR, Harker LA, Johnson RJ, Merritt K, Naylor PT, Schoen FJ. Host reactions to biomaterial and their evaluation. In: Ratner BD, Hoffman AS, Schoen FJ, Lemons JE, editors. Biomaterials science: An introduction to materials in medicine. San Diego, CA: Academic Press; 1996. p. 127-46.