Molecular Events in the Foreign Body Response

Figure 1

When biomaterial and medical devices are surgically implanted into the body, a series of molecular and cellular events lead to its encapsulation and isolation from surrounding tissue. This series of events is known as the Foreign Body Reaction ( FBR) and can limit the device's overall biocompatibility and function. Every foreign surface first acquires a protein coat when within the body, composed of fibrinogen, albumin, fibronectin and other blood and interstitial-fluid proteins. The edema caused by the surgical procedure of implantation and several chemoattractants lead to leukocyte emigration from the blood and accumulation in the biomaterial site. Together with platelets, leukocytes bind on to the protein-coated surface.  Neutrophils have a short lifetime of about 2 days, while macrophages stay in the site for much longer. 

Around day 6/7 after implantation of the medical device, small multinucleated Foreign Body Giant Cells (FBGC) appear on the surface of the biomaterial. These cells can grow to include more than 100 nuclei since they are the result of robust macrophage fusion. Their phagocytic potential far exceeds that of all their component macrophages individually due to their ability to degrade targets extr acellularly (extroversion), and they are very similar to osteo clasts w hich arise from the same cellular precursor in the bone marrow. Both FBGC and macrophages secrete fibroblast attractants, and the incoming fibroblasts play a key role in creating a dense and organized collagenous matrix around the biomaterial, that has very low vasculature density. 

It is important to note that this matrix deposition is quite different from the regular process of healing, and the Foreign Body Response has a lot of characteristics that occur in the fibrotic process during a chronic inflammation. This ECM capsule isolates medical devices from the rest of the interstitial tissue and can also often contract, leading to adverse effects for the medical device function.

Figure 2
In vitro three-dimensional angiogenesis assay. Endothelial cells are placed in a collagen gel and form chords resembling blood vessels. Image shows cells stained with DAPI (blue nuclei), phalloidin (actin cytoskeleton). Green fluorescence is indicative of matrix metalloproteinase activity, which is required for angiogenesis.
Figure 3 - Thrombospondin

Thrombospodin

Thrombospondin (TSP)-2 is an inhibitor of angiogenesis with pro-apoptotic and anti-proliferative effects on cultured endothelial cells. As a matricellular protein, TSP2 can modulate cell-matrix interactions and influence a number of processes including recovery from ischemia, wound healing, and the foreign body response. TSP2 has been shown to interact with a number of cell surface receptors, growth factors, extracellular matrix components, and enzymes. Thus, its participation in biological processes is thought to be complex.