Bioscience and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, United States.
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
ACS Appl Mater Interfaces. 2021 Aug 11;13(31):37873-37882. doi: 10.1021/acsami.1c09245. Epub 2021 Jul 30.
Calcium oxalate monohydrate (COM) crystal is the most common crystalline component of human kidney stones. The molecular-scale inhibitory mechanisms of COM crystal growth by urinary biomolecules such as citrate and osteopontin adsorbed onto the crystal surface are now well understood. However, the pathways by which dissolved calcium and oxalate ions are incorporated into the molecular step of the COM crystal surface, leading to COM crystal growth-a prerequisite to be elucidated for developing effective therapeutics to inhibit COM stones-remain unknown. Here, using in situ liquid-phase atomic microscopy along with a step kinetic model, we reveal the pathways of the calcium and oxalate ions into the COM molecular step via the growth speed analysis of the molecular steps with respect to their step width at the nanoscale. Our results show that, primarily, the ions are adsorbed onto the terrace of the crystal surface from the solution-the rate-controlling stage for the molecular step growth, i.e., COM crystal growth-and then diffuse over it and are eventually incorporated into the steps. This primary pathway of the ions is unaffected by the model peptide D-Asp adsorbed on the COM crystal surface, suggesting that urinary biomolecules will not alter the pathway. These new findings rendering an essential understanding of the fundamental growth mechanism of COM crystal at the nanoscale provide crucial insights beneficial to the development of effective therapeutics for COM kidney stones.
一水合草酸钙（COM）晶体是人类肾结石中最常见的结晶成分。现在，人们已经很好地理解了尿液生物分子（如柠檬酸盐和骨桥蛋白）吸附在晶体表面对 COM 晶体生长的分子尺度抑制机制。然而，溶解的钙离子和草酸根离子是如何进入 COM 晶体表面的分子台阶，从而导致 COM 晶体生长的途径——这是开发有效抑制 COM 结石治疗方法所必需阐明的——仍然未知。在这里，我们使用原位液相原子显微镜和一个阶跃动力学模型，通过纳米尺度上分子台阶的阶宽与其生长速度的分析，揭示了钙离子和草酸根离子进入 COM 分子台阶的途径。我们的结果表明，首先，离子从溶液中被吸附到晶体表面的平台上，这是分子台阶生长的速率控制阶段，即 COM 晶体生长，然后在其上扩散，并最终被纳入台阶。这种离子的主要途径不受吸附在 COM 晶体表面的模型肽 D-Asp 的影响，这表明尿液生物分子不会改变途径。这些新发现对理解 COM 晶体在纳米尺度上的基本生长机制提供了至关重要的认识，有助于开发有效的 COM 肾结石治疗方法。
