Molecular modifiers reveal a mechanism of pathological crystal growth inhibition

Like citrate, the molecule hydroxycitrate is shown to inhibit growth of the crystal that is the principal component of kidney stones, suggesting that hydroxycitrate could be another treatment for kidney stone disease. Novel inhibitor action on 'kidney stone' crystal growth This paper reports that both citrate and hydroxycitrate molecules are able to inhibit growth of crystals of calcium oxalate monohydrate — the principal component of kidney stones — even in a supersaturated solution where the inhibitor concentration is far smaller than the concentration of the solutes. The mechanism for crystal growth inhibition diverges from the classical picture of such processes: atomic force microscopy images and other data point to a mechanism in which inhibitor–crystal interactions impart localized strain to the crystal lattice that are alleviated by oxalate and calcium ions. Potassium citrate is an established treatment for kidney stone disease and the authors suggest that the clinical potential of hydroxycitrate might also be worth exploring and report preliminary in vitro investigations to support this suggestion. Crystalline materials are crucial to the function of living organisms, in the shells of molluscs 1 , 2 , 3 , the matrix of bone 4 , the teeth of sea urchins 5 , and the exoskeletons of coccoliths 6 . However, pathological biomineralization can be an undesirable crystallization process associated with human diseases 7 , 8 , 9 . The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules 10 , 11 to large macromolecules 12 . Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth 13 , 14 . Complex inhibitor–crystal interactions in biomineralization are often not well elucidated 15 . Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization—citrate and hydroxycitrate—exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a h