The use of biomaterials and implants for joint replacement, fracture fixation, spinal stabilization and other orthopedic indications has revolutionized patient care by reliably decreasing pain and improving function. These surgical procedures always invoke an acute inflammatory reaction initially, that in most cases, readily subsides. Occasionally, chronic inflammation around the implant develops and persists; this results in unremitting pain and compromises function. The etiology of chronic inflammation may be specific, such as with infection, or be unknown. The histological hallmarks of chronic inflammation include activated macrophages, fibroblasts, T cell subsets, and other cells of the innate immune system. The presence of cells of the adaptive immune system usually indicates allergic reactions to metallic haptens. A foreign body reaction is composed of activated macrophages, giant cells, fibroblasts, and other cells often distributed in a characteristic histological arrangement; this reaction is usually due to particulate debris and other byproducts from the biomaterials used in the implant. Both chronic inflammation and the foreign body response have adverse biological effects on the integration of the implant with the surrounding tissues. Strategies to mitigate chronic inflammation and the foreign body response will enhance the initial incorporation and longevity of the implant, and thereby, improve long-term pain relief and overall function for the patient. The seminal research performed in the laboratory of Dr. James Anderson and co-workers has provided an inspirational and driving force for our laboratory's work on the interactions and crosstalk among cells of the mesenchymal, immune, and vascular lineages, and orthopedic biomaterials. Dr. Anderson's delineation of the fundamental biologic processes and mechanisms underlying acute and chronic inflammation, the foreign body response, resolution, and eventual functional integration of implants in different organ systems has provided researchers with a strategic approach to the use of biomaterials to improve health in numerous clinical scenarios.
Macrophages derive from human embryonic and fetal stem cells and from human bone marrow-derived blood monocytes. They play a major homeostatic role in tissue remodeling and maintenance facilitated by apoptotic "eat me" opsonins like CRP, serum amyloid P, C1q, C3b, IgM, ficolin, and surfactant proteins. Three subsets of monocytes, classic, intermediate, and nonclassic, are mobilized and transmigrate to tissues. Implant-derived wear particles opsonized by danger signals regulate macrophage priming, polarization (M1, M2, M17, and Mreg), and activation. CD14(+) monocytes in healthy controls and CD16(+) monocytes in inflammation differentiate/polarize to foreign body giant cells/osteoclasts or inflammatory dendritic cells (infDC). These danger signal opsonins can be pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), but in aseptic loosening, usually are damage-associated molecular patterns (DAMPs). Danger signal-opsonized particles elicit "particle disease" and aseptic loosening. They provide soluble and cell membrane-bound co-stimulatory signals that can lead to cell-mediated immune reactions to metal ions. Metal-on-metal implant failure has disclosed that quite like Ni(2+), its neighbor in the periodic table Co(2+) can directly activate toll-like receptor 4 (TLR4) as a lipopolysaccharide-mimic. "Ion disease" concept needs to be incorporated into the "particle disease" concept, due to the toxic, immune, and inflammatory potential of metal ions.
