These cells can differentiate into osteoblasts under the influence of Bone morphogenetic protein BMP -2, which apart from osteogenesis also stimulates angiogenesis in bone healing. Under the condition of low oxygen tension the progenitor cells may also differentiate into chondrogenic cells.
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Osteoblasts , derived from osteoprogenitor cells synthesize the organic components of the bone, such as collagen, proteoglycan and glycoproteins Fig. After their differentiation they express bone specific alkaline phosphatase ALP , which therefore, is a late marker of bone formation. Osteocytes derived from osteoblasts are mature bone cells, that became trapped in their lacunae. Osteocytes keep in contact to each other by cytoplasmatic processes, through which ions and small molecules can move between the cells [ 70 ].
Cells responsible for bone or material resorption are connected to the osteoclast lineage. The precursor cells of osteoclasts come from the bone marrow and are called granulocyte-macrophage progenitor cells [ 71 ]. They are thought to derive from the blood macrophages. Upon stimulation by local signalling molecules, mediators and cytokines such as receptor activator of nuclear factor-B ligand RANKL , prostaglandin E2, interleukin IL -1 and 6 these originally mononuclear cells fuse to become multinucleated cells generally found on mineralized surfaces in bone Fig.
It is not always possible to distinguish osteoclasts from foreign body cells FBGC with certainty. Osteoclasts resemble foreign body giant cells morphologically but have calcitonin receptors on their surface. To distinguish osteoclasts from FBGCs immunostaining of osteocalcin receptors would, therefore, be the modern method of choice.
Some authors found out, that the TRAP-coloration was not entirely specific for osteoclasts [ 73 ]. However, technical problems with immunostainings in bone especially in larger animal species and in combination with biomaterials, where bone samples have to be embedded in plastic sections, make it impossible to successfully use osteocalcin antibodies for osteoclast identification. Osteoclasts degrading a natural bone substitute material arrows.
Kossa 20x, Toluidinblue 10x. Osteoclasts can carry out the highly specialized function of lacunar bone resorption, but it is generally believed that they do not phagocytose particles of biomaterials at the bone-implant interface [ 74 ]. However other investigations show, that they are capable of phagocytosing both polymeric and metallic biomaterial particles.
This lead to the conclusion, that not all multinucleated cells, that contain wear particles and can be found next to osteolysis are FBGC [ 75 ]. In the line of defense, lymphocytes and plasma cells produce antibodies to protect the body against foreign antigens, they are seen in greater numbers in areas of more chronic inflammation and where foreign substances have entered the tissue [ 56 , 65 , 68 , 69 , 76 - 80 ] Fig.
Neutrophils participate in the foreign body reaction by releasing lytic enzymes [ 81 ]. Usually neutrophil polymorphs are found in the immediate period after lesions were created for wound debridement, but mark the presence of sub- clinical bacterial infection if found later in the wound healing period. In addition, two other cell types are also especially interesting considering cellular defense mechanism to foreign material: macrophages and foreign body giant cells FBGC.
There is no general agreement in the literature about their character of being inflammatory and thus, negative for the process, or just belonging to a normal response in degrading materials. All members of that system arise from a common stem cell in the bone marrow, possess lysosomes and are capable of phagozytosis. In the first few days after a fracture has occurred or a bone defect has been produced, granulation tissue grows in between the fracture ends or edges respectively.
As mentioned above, neutrophil polymorphs are the type of cells which can be found most frequently in this period. The macrophage derived interleukin-1 may cause neutrophil infiltration, induce angiogenesis and antibody production and lymphokine synthesis [ 82 ]. Later more chronic inflammatory cells like macrophages are found, which remove red cells, necrotic fat and tissue debris [ 76 ].
They adhere to the biomaterials via several adhesion ligand-receptor superfamilies [ 80 ], such as with an integrin binding [ 68 ]. Certain biomaterial-adsorbed proteins promote monocyte adhesion. The most active in this regard are fibrinogen, fibronectin and immunglobulin G [ 85 - 87 ]. After adhesion they transform into macrophages which are characterized by cell enlargement and an increased secretion of inflammatory mediators cytokines and chemokines , an increased expression of membrane proteins e. The released factors attract different cell types like additional macrophages, neutrophils, fibroblasts and other cells [ 89 - 92 ].
Macrophages are cells that secrete factors to promote physiological wound healing. Some of the macrophages may also function as accessory antigen-presenting cells [ 93 ]. On the other hand, they can be the central cellular mediators of the chronic inflammatory response to foreign materials [ 56 ] by secreting monocyte chemoattractant protein-1 MCP-1 contributing to the development of the foreign body reaction [ 94 ], disturbing wound healing and ultimately contributing to implant failure. Macrophages phagocytose damaged cells, cellular debris and foreign substances and digest the ingested material by hydrolytic enzymes in their lysosomes.
While this mechanism functions for several biomaterials in the same way, their enzymatic apparatus is not able to degrade synthetic polymers [ 95 ]. Some authors consider the presence of macrophages around or near biomaterials to be part of a chronic inflammatory reaction, whereas others relate to them as part of the normal degradation behaviour, at least in case of degradable materials in bone [ 27 , 62 , 96 , 97 ] Fig.
Biocompatibility study of a biomaterial as bone substitute in sheep bone. Macrophages arrows with ingested foreign material. Macrophages also modulate the tissue reaction through production of interleukins, growth factors and other bioactive agents and most importantly they are the precursors of osteoclasts and foreign body giant cells. The role of RANKL and what triggers the fusion and further differentiation into osteoclasts or foreign body giant cells is not entirely clear [ 96 , 97 ].
This effect leads to bone resorption and in excess can induce implant failure [ ]. While in debate whether osteoclasts contain foreign material in their cytoplasm, it also has been shown, that macrophages, which have phagocytosed particles, are capable of osteoclast differentiation [ ]. Interaction of macrophages and lymphocytes are complementary. It is likely that the adhesion of macrophages to a surface also is the initial signal to activate the lymphocytes which in turn release molecules that furthermore influence macrophage activity [ 77 ] and fusion [ 81 , - ].
Therefore, the presence and activity of lymphocytes may be a determining factor in excessive resorption behaviour or ultimate biocompatibility questions. Macrophages also modulate in the process of tissue repair. Since they derive from the vascular system, a good vascularity, therefore, is one of the important factors [ ]. Animals depleted of macrophages or having received antimacrophage monoclonal antibodies show deficient wound healing [ ].
In case of biomaterials and bone controversy exists in whether they are part of normal bone healing or material degradation, or whether they play a significant role in issues of bioincompatibility. His view in regard to foreign bodies is similar to Lassus et al. The mechanism of cellular fusion of macrophages to FBGC is similar to phagocytosis and is mediated by several mediators [ , ], but little is known regarding the biological responses which are considered to influence the transition to FBGC development [ 69 ].
It can lead to very large cells up to 1 mm 2 with hundreds of nuclei [ , ]. FBGCs are also generally observed in granulomas induced by bacterial pathogens, such as in tuberculosis or trichinellosis, which is probably the main reason for the negative association with their presence in tissue. Cytokines like interleukin-4 and 13 are known as potent inductors of macrophage fusion into FBGC [ , , ]. They also play a central role in cellular reactions which cause bone lysis around implants [ ] as they modulate the balance between osteoblasts and osteoclasts [ ].
The injection of anti-interleukinantibody significantly decreased FBGC density on polyetherurethane ureas in vivo [ ].
Foreign body giant cells act to concentrate phagocytic and degradative activities at the host-implant interface. They ingest and dissolute implanted material intracellularly or by the release of degradative agents like lysosomal enzymes and reactive oxygen intermediates ROIs at the ventral cell surface [ ] in response to certain stimuli, whereby their phagocytic capacity can be as effective as macrophages [ ].
Biocompatibility Issues with Modern Implants in Bone - A Review for Clinical Orthopedics
They also can directly contribute to osteolysis by differentiation into TRAP-positive osteoclast-like cells [ - ]. FBGC rapidly differentiate after the implantation and progressively decrease with time [ ]. Their size depends on the intensity of the inflammatory response [ ]. FBGCs contain great numbers of mitochondria of various size and oval or round nuclei. Rough endoplasmatic reticulum is found throughout the cytoplasm [ ]. The osteoclast on the other hand is defined as possessing a resorbing apparatus consisting of ruffled border and clear zone, expression of the tartrat—resistant acid phosphatase and the expression of calcitonin-receptors [ ].
However, it has to be kept in mind that other authors question whether the TRAP-epitopes as well as other markers such as calcitonin receptors are specific for osteoclasts [ 73 ]. One of the most important aspects in the evaluation of biomaterials is the degradation resistance, with the exception of the class of biodegradable polymers, that rely on enzymes, acid or ROIs for degradation of the polymer matrix [ ]. The discussion about the role of FBGCs is controversary with the main question being whether the presence of FBGCs near an implant is just a sign of biodegradability [ ], therefore a part of normal bone healing and resorption after the implantation of a bone substitute, or a sign of insufficient biocompatibility, inflammation and implant failure?
Both sides have valuable arguments ready which are outlined below. The arguments in favour of the FBGC are that i these cells are part of the normal wound healing response to implanted inert or biodegradable biomaterials [ 56 , ], ii their presence does not impair bone formation [ 31 ], iii the presence of FBGCs indicates a low degradability of the implanted substance [ , , ], iv FBGC in the absence of other inflammatory cells show a good biocompatibility [ ], and most importantly v macrophages and FBGCs mediate material resorption and fragmentation of biodegradable implants [ , - ].
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The latter is supported through the fact that resorbed material could be seen in intracytoplasmatic vacuoles by transmission electron microscopy [ ]. This view, that FBGC are responsible for the degradation of biomaterials, is further supported by the analyses of retrieved implants showing material surface cracks directly under adherent FBGC [ ].
If macrophages and foreign body cells are part of the normal wound healing process, the foreign body cells may persist for the lifetime of the implant, it is not known if activated or quiescent [ 69 ]. Here, the question arises where the line has to be drawn for local tissue tolerance?
The arguments pointing towards FBGC being a a bad sign for tissue tolerance are that i the fusion of specialized macrophages is induced by poorly tolerated foreign bodies [ 78 , , ], ii avoiding monocyte or macrophage adhesion and FBGC formation, inflammatory degradation could be minimized [ ], iii the presence of macrophages and FBGC is associated with structural and functional failure of the implant [ ], and iv FBGC seem to concentrate the phagocytic and degradative activities at the tissue-material interface and therefore are responsible for the damage and failure of the implant.
For the latter the authors tested coating the surface of an implant with a material that promotes programmed cell death to inhibit the adhesion and fusion of macrophages into FBGCs [ ].
This can be achieved best by a layer of FBGC in a fibrous, quite avascular capsule limiting further interaction between host and implanted device. The capsule type depends on the secreted cytokines [ 95 , ], the extent of injury or defect created and the amount of provisional matrix [ 69 ]. On one hand this fibrous capsule may indeed downsize the inflammatory reaction, but on the other hand in osseointegration processes can lead to device failure and restricted nutrient supply. Poor tissue device contact can lead to infection.