Mechanisms of Modulation of Calcium Phosphate Pathological Mineralization by Mobile and Immobile Small-Molecule Inhibitors

Abstract

Potential pathways for inhibiting crystal growth are via either disrupting local microenvironments surrounding crystal-solution interfaces or physically blocking solute molecule attachment. However, the actual mode of inhibition may be more complicated due to the characteristic time scale for the inhibitor adsorption and relaxation to a well-bound state at crystal surfaces. Here we demonstrate the role of citrate (CA) and hydroxycitrate (HCA) in brushite (DCPD, CaHPO·2HO) crystallization over a broad range of both inhibitor concentrations and supersaturations by in situ atomic force microscopy (AFM). We observed that both inhibitors exhibit two distinct actions: control of surface crystallization by the decrease of step density at high supersaturations and the decrease of the [1̅00] step velocity at high inhibitor concentration and low supersaturation. The switching of the two distinct modes depends on the terrace lifetime, and the slow kinetics along the [1̅00] step direction provides specific sites for the newly formed dislocations. Molecular modeling shows the strong HCA-crystal interaction by molecular recognition, explaining the AFM observations for the formation of new steps and surface dissolution along the [101] direction due to the introduction of strong localized strain in the crystal lattice. These direct observations highlight the importance of the inhibitor coverage on mineral surfaces, as well as the solution supersaturation in predicting the inhibition efficacy, and reveal an improved understanding of inhibition of calcium phosphate biomineralization, with clinical implications for the full therapeutic potential of small-molecule inhibitors for kidney stone disease.

Engaging a Battle on Two Fronts: Dual Role of Polyphosphates as Potent Inhibitors of Struvite Nucleation and Crystal Growth

“…This is then followed by a return to a higher step density, but with steps advancing from the bottom right that are comprised of corrugated edges (Figure 6C). According to classical nucleation theory, the free energy of the system is governed by the solution supersaturation and the free energy of the step edge [51][52][53][54] . At the conditions used for in situ AFM, the concentration of HMP is too small to lower supersaturation via its sequestration of free Mg 2+ ions (i.e.…”

Whitlockite structures in kidney stones indicate infectious origin: a scanning electron microscopy and Synchrotron Radiation investigation

“…For further insight into the relationship between infection and kidney stones containing Wk without struvite, we have used physicochemical characterization techniques [29][30][31][32] to obtain a precise multiscale description of such concretions [33][34][35][36][37]. First, by analogy with geological studies [38], we assessed the presence of iron in Wk by X-ray fluorescence (XRF) [39][40][41] using synchrotron radiation (SR) as a probe [42][43][44][45][46].…”

Phosphoserine Functionalized Cements Preserve Metastable Phases, and Reprecipitate Octacalcium Phosphate, Hydroxyapatite, Dicalcium Phosphate, and Amorphous Calcium Phosphate, during Degradation, In Vitro

“…These chelators improve the mechanical strength by reducing the crystal size, and extending the working/setting time. However, chelators produce a monomeric organic phase that binds to the mineral surface [16][17][18][19][20], rather than a molecularly intermixed composite [6,10] with macroscale interactions (i.e., polymeric or crosslinking) [21][22][23][24].…”