(379a) Surface Dynamics of Calcium Oxalate Monohydrate Crystallization: Elucidating Mechanisms of Growth Inhibition

Calcium oxalate monohydrate (COM) crystals are the primary constituent of human kidney stones. The growth of these crystals in vivo is affected by different urinary constituents (e.g., ions and molecules), which act as modifiers by adsorbing onto different sites of the crystal surface, thereby influencing the rate(s) of anisotropic crystal growth with concomitant alterations in crystal size and habit.^1-2 At the molecular level, COM crystals grow classically (i.e. monomer-by-monomer addition) where single layers nucleate and advance across the surface by solute addition to surface sites (e.g. kinks, steps, or terraces).³ Modifiers can alter crystal growth by adsorbing onto surfaces and blocking solute attachment and/or by complexing with free monomers in solution to reduce supersaturation (i.e., the primary driving force for crystal growth).⁴ In order to design drugs that inhibit crystallization, it is critical to understand their modes of action. To this end, we conducted in situ atomic force microscopy to probe the effect of naturally occurring and synthetic modifiers on the dynamics of surface growth as a function of supersaturation and modifier concentration. Our studies reveal unique modes of action that vary significantly based on subtle differences in the physicochemical properties of modifiers⁵. Here, we will discuss the results of our studies and demonstrate how these techniques serve as a useful platform for the design of new generation therapeutics to treat diseases such as kidney stones.

1. Farmanesh, S.; Alamani, B. G.; Rimer, J. D., Identifying alkali metal inhibitors of crystal growth: a selection criterion based on ion pair hydration energy. Chemical Communications 2015, 51 (73), 13964-13967.

2. Farmanesh, S.; Ramamoorthy, S.; Chung, J. H.; Asplin, J. R.; Karande, P.; Rimer, J. D., Specificity of Growth Inhibitors and their Cooperative Effects in Calcium Oxalate Monohydrate Crystallization. Journal of the American Chemical Society 2014, 136 (1), 367-376.

3. Chung, J.; Granja, I.; Taylor, M. G.; Mpourmpakis, G.; Asplin, J. R.; Rimer, J. D., Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature 2016, 536 (7617), 446-450.

4. Olafson, K. N.; Li, R.; Alamani, B. G.; Rimer, J. D., Engineering Crystal Modifiers: Bridging Classical and Nonclassical Crystallization. Chem Mater 2016.

5. Farmanesh, S.; Chung, J. H.; Sosa, R. D.; Kwak, J. H.; Karande, P.; Rimer, J. D., Natural Promoters of Calcium Oxalate Monohydrate Crystallization. Journal of the American Chemical Society 2014, 136 (36), 12648-12657.