The Materials Science of Pathological Crystals

Abstract

Aberrant crystallization within the human body can lead to several disease states, although traditionally the pathogenesis of such diseases has not been studied from a materials science perspective. A fundamental understanding of the nucleation and growth, sometimes followed by aggregation and adhesion of crystals to tissue, is essential for the elucidation of the mechanisms directing the pathogenesis of these diseases. The quest for a greater understanding of these in vivo events has prompted the use of innovative experimental approaches aimed at understanding them at a microscopic level, often under conditions thought to emulate a physiological environment. Real-time, in situ atomic force microscopy (AFM) has been used to elucidate the effect of urinary substituents on calcium-containing crystals that aggregate to form kidney stones, demonstrating the role of anionic proteins, synthetic polymers and small molecules on crystal growth regulation. Through an understanding of the structure of l-cystine crystals, which produce a rare and severe form of kidney stones, intermolecular interactions necessary for the growth of these crystals were identified and molecular inhibitors were designed that bind stereospecifically to actively growing crystal faces, thereby suppressing growth. X-ray diffraction techniques have been used to investigate the nucleation of cholesterol crystals within lipid membranes, providing insight into the formation of atherosclerotic plaques and crystals that can aggregate to form gallstones. The discovery of the crystal structure of hemozoin, which results from the crystallization of free heme within the digestive vacuole of the prevalent malaria parasite Plasmodium falciparum, combined with grazing angle X-ray diffraction and other methods, has informed on the mode of action of common antimalarial drugs, providing guidance for the development of new therapies that can overcome the increasing resistance of the parasite to current drugs. The role of materials science in the study of pathological conditions is expected to become increasingly significant as crystal growth theory, solid-state chemistry, and materials characterization methods are applied to a greater breadth of disorders, ranging from crystalline amyloid proteins associated with neurodegenerative diseases to unwanted in vivo crystallization of administered pharmacological compounds.