Nanobacteria: fact or fiction? Characteristics, detection, and medical importance of novel self-replicating, calcifying nanoparticles.

Including humans, many multicellular organisms produce similar hard tissues, such as bones, teeth, shells, skeletal units, and spicules. These hard tissues are biocomposites and incorporate both structural macromolecules (lipids, proteins, and polysaccharides) and inorganic minerals. We do not fully understand the control mechanism of biomineralization in primitive or in developed organisms. The mineral phase of hard tissue is sometimes called biologic apatite, that is, a nonstoichiometric hydroxylapatite. Pure hydroxyapatite has the formula Ca10(PO4)6(OH)2. In contrast, a biologic apatite (like in bone) is nonstoichiometric and contains several other ions, mainly carbonate and other elements in traces such as Mg, Na, Fe, HPO4 , F, and Cl. Consequently, a more appropriate structural formula for the composition of bone is (Ca,X)10(PO4,CO3,Y)6(OH,Z)2, with X substituting cations and Y and Z substituting anions (with the indices 10, 6, and 2 changing according to stoichiometry). There is a paradox in medicine. Whereas some researchers have been discussing the cytotoxic effect of apatite in vitro, others have been announcing the safety of in vivo apatite applications. Although these disagreements have not been completely resolved, both biogenic and nonbiogenic apatite materials have been continuously used in drug delivery and transplantation. We know that when apatite is found in soft tissue, it is considered to be pathologic calcification. The causes of apatite-deposit formations in soft tissue have been discussed for decades but still remain speculative. For example, calcification in the coronary arteries has been widely regarded as an uncommon, end-stage, insignificant, passive, degenerative process of aging—a notion that has paralyzed research in this area for decades. Interestingly, these same terms were once used to describe atherosclerosis. Today, we know that coronary artery calcification occurs, almost exclusively, at sites of atherosclerotic lesions. Calcification in the development of these plaques is a complicated, actively regulated process of mineralization that is similar to bone formation and remodeling. Mineralogists explain that all that is needed for crystal formation/biomineralization to start is nidi (nucleus) and an environment of available dissolved components at or near saturation concentrations, along with the absence of inhibitors for crystal formation. Bacteria or other agents producing such nidi, if present in blood and in urine, are very likely candidates to launch and accelerate pathologic calcification in vivo. This is clinically important because blood contains phosphate near its saturation level.