Host Response to Foreign Materials

After the implantation procedure, the body follows a sequence of local events during the healing response. These are acute inflammation, chronic inflammation, granulation tissue formation, foreign body reaction, and fibrosis. The steps and predominant cell types present during these steps of wound healing are shown in Fig. 1 (Karlsson et al. 2004).

Inflammation is the reaction of vascularized living tissue to local injury. It activates a series of events which may heal tissue after implantation by recruiting parenchymal cells or cells intended to encapsulate the implant with fibrous tissue. The initial inflammatory response is activated regardless of the type of biomaterial and the location of injury. Acute inflammation is a short-term (few days) response to the injury. Immediately after the surgery, the blood flow to the injury site increases. This implies an increased flow of proteins (some of them can promote anchorage-dependent cell attachment), nutrition, immune cells, cells that can help recovery, mesenchymal stem cells, etc. The first cells to appear at the implantation site are white blood cells, mainly neutrophils. Afterwards, neutrophils recruit monocytes to the inflammation area (where monocytes will further differentiate into macrophages which are well known to aid in implant material degradation). Neutrophils are then recruited to the site of inflammation by chemical mediators (chemotaxis) to phagocytose microorganisms and foreign materials (Anderson et al. 1996). They attach on the surfaces of the biomaterial by adsorbed proteins, basically immunoglobulin G (IgG) and complement-activated fragments (such as C3b) through a process called "opsonization." Due to the relative size difference between biomaterials and phago-cytotic cells, cells clearly cannot internalize the implant. This leads to a condition called "frustrated phagocytosis," which is the activation of phagocytic cells to produce extracellular products that attempt to degrade the biomaterial and, at the same time, recruit more cells to the implant site. Macrophages then secrete degradative

—ACUTE-CHRONIC—GRANULATION TISSUE-

—ACUTE-CHRONIC—GRANULATION TISSUE-

Fibrosis

Mononuclear

Leucocytes

Fibroblasts

Macrophages Neovascularization

Foreign Body Giant Cells

Time

(Minutes, Hours, Days, Weeks)

Fig. 1 Time vs. intensity graph for the wound healing responses showing the predominant cell types at the inflammation site. (Adapted and redrawn from (Karlsson et al. 2004))

Neutrophils

Fibrosis

Mononuclear

Leucocytes

Fibroblasts

Macrophages Neovascularization

Foreign Body Giant Cells

Time

(Minutes, Hours, Days, Weeks)

Fig. 1 Time vs. intensity graph for the wound healing responses showing the predominant cell types at the inflammation site. (Adapted and redrawn from (Karlsson et al. 2004))

agents (such as superoxides and free radicals) which severely damage both the juxtaposed tissue and possibly the implant.

A persistent inflammatory response leads to chronic inflammation (Anderson et al. 1996). The main cell types observed during chronic inflammation are monocytes, macrophages, and lymphocytes. Neovascularization (formation of new blood vessels) also starts during this step of wound healing. Macrophages are the most important type of cells in chronic inflammation due to the secretion of a great number of biologically active products such as: proteases, arachidonic acid metabolites, reactive oxygen metabolites, coagulation factors, and growth factors (which are important to recruit and promote fibroblast functions).

The third step in the foreign body response is granulation tissue formation. Fibroblasts form granulation tissue. This tissue is the hallmark of the healing response. It is granular in appearance and contains many small blood vessels (Maki and Tambyah 2001). In addition, macrophages fuse together to form foreign body giant cells to attempt to phagocytose the foreign materials much more effectively. The amount of granulation tissue determines the extent of fibrosis.

The foreign body reaction, the fourth step in wound healing, contains foreign body giant cells and granulation tissue (which includes fibroblasts, capillaries, macrophages, etc.). Biomaterial surface properties are the key determining factor in this step. It has been shown that smooth surfaces (micron smooth) induce a foreign body reaction which is composed of macrophages one to two cells in thickness (Anderson et al. 1996). However, as the roughness (micron rough) increases, so does the foreign body reaction.

The last step in the wound healing response is fibrosis, which is the fibrous tissue encapsulation of the implant. The successfulness of implantation generally depends on the proliferation capacity of the cells in the tissue. Tissues containing labile (proliferate throughout time) or stable (expanding) cells are less likely to have entered the fibrosis step. However, if the cells comprising that tissue are stable (not growing, limited proliferation capacity), the chances of fibrous tissue formation are relatively higher. As stated before, fibrous encapsulation is not desired in bone tissue engineering applications because it leads to failure of the implant due to stress-strain imbalances. Quite simply, fibrous tissue cannot support physical stresses that some tissues can (like bone or cartilage). The desired situation for an orthopedic implant is the recruitment of parenchymal cells, around the implant as soon as possible.

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