Chondroyte desensitization to mechanical loading

该研究计划的总体目标是研究软骨细胞对机械载荷脱敏的机制，并开发提高细胞敏感性的方法。机械刺激是促进组织工程软骨生长的一种广泛应用的方法。然而，由于这些细胞对负载迅速脱敏，这种方法的有效性是有限的。虽然最近的研究表明，细胞对机械负荷脱敏的潜在原因与细胞内钙有关，但细胞钙的调节是复杂的，因为钙参与了几个细胞间的功能和过程。通过对机械负荷过程中细胞内钙信号的研究，将有可能确定细胞脱敏的根本原因，并确定提高细胞敏感性的方法。此外，减轻细胞脱敏效应的另一种方法是通过修改应用的加载协议。具体来说，细胞对机械刺激的敏感性可以通过在加载波形上叠加机械振动（噪声）来改变。这种方法被称为“随机共振”，已经成功地应用于提高其他非线性生物医学系统的灵敏度，包括相同谱系的机械敏感细胞（例如骨细胞）。虽然我们的初步研究表明，这种方法有可能限制软骨细胞负荷诱导的脱敏，但其影响程度以及潜在的机制尚未确定。

The overall goal of the proposed research program is to investigate the mechanisms responsible for the desensitization of cartilage cells to mechanical loading, and to develop methods to improve cellular sensitivity. The application of mechanical stimuli is a widely used method to enhance the growth of tissue engineered cartilage. However, as these cells rapidly desensitize to loading, the effectiveness of this approach is limited. While recent work has suggested that the potential cause of cellular desensitization to mechanical loading is related to intracellular calcium, the regulation of cellular calcium is complex as calcium is involved in several intercellular functions and processes. Through the study of intracellular calcium signaling during mechanical loading, it will be possible to identify the underlying cause of cellular desensitization and identify methods to improve cellular sensitivity. In addition, an alternative approach to mitigate the effects of cellular desensitization is through the modification of the applied loading protocols. Specifically, cellular sensitivity to mechanical stimuli can be altered by superimposing mechanical vibrations (noise) on the loading waveforms. This approach, termed “stochastic resonance”, has been successfully applied to improve sensitivity in other nonlinear biomedical systems including mechano-sensitive cells of the same lineage (e.g. osteocytes). While our preliminary studies have shown that this approach has the potential to limit loading-induced desensitization in chondrocytes, the extent of its effect as well as the underlying mechanisms responsible, have yet to be determined.