Search

Introduction: Drug induced cardiotoxicity is a major cause of market withdrawal. The limited availability of human heart tissue has led to inaccurate interpretations of cardiac related drug effects. Our group had developed a culture system for pig/human heart slices that is functionally and structurally viable 6 days under electric stimulation and enriched media and could reliably demonstrate the subacute toxic effect of anti-cancer therapeutics. However, by day 10, the slices underwent cardiomyocyte dedifferentiation and fibrotic remodeling, making them inadequate for long-term cardiotoxicity testing. Aims: Including physiological mechanical and humoral cues within the culture system can prolong the viability of the human heart tissue in culture. Methods and Results: Following small molecule screening, we found that incorporation of 100 nM Tri-iodo-thyronine (T3) and 1 μM Dexamethasone (Dex) into our culture media preserved microscopic structure for 12 days in pig and human slices. However, RNA sequencing revealed a significant down regulation in cardiac contractile genes as early as day 8 in culture. To address this, we developed a novel bioengineered Cardiac Tissue Culture Model (CTCM) that can electro-mechanically stimulate heart slices with physiological preload and afterload during each cardiac cycle (Figure 1). Transcriptionally, combining CTCM with T3/Dex treatment, CTCM system was able to maintain the cardiac contractile gene expression at the same levels as the fresh hear tissue. Functionally, heart slices cultured in our CTCM with T3/Dex treatment, completely preserved structural viability and metabolic activity for 12 days. Conclusion: This study demonstrates a new physiological culture system for human heart slices that provides physiological mechanical and humoral cues for maintaining viability and functionality of the heart slices. CTCM may be an ideal platform for chronic cardiotoxicity testing.

As a kind of slim shell structure flexibly based on its deformable foundation, high concrete arch dam exhibits remarkable spatial–time characteristics. In this paper, the Xiaowan Hydropower Project accommodating 294.5 m high double curvature arch dam is taken as example, to which the factor of time is introduced in the whole numerical simulation procedure. The dynamic inputting of the parameters related to the structural geometry and material properties (e.g. thermal, permeability, deformation/stress) following the construction progress is realized in an intension to establish a four-dimensional (spatial–time) numerical simulation procedure. The Digitized System of Xiaowan Arch Dam (DSXAD) is further formulated by the combination of the instrumentation system, the spatial–time simulation procedure, and the engineering judgments. The DSXAD has been working well in tracing the real working status of the dam during its construction period as well as service period. A series of difficult technical issues in the construction of the Xiaowan Dam are successfully solved with the help of the DSXAD. Through this practices important theoretical insights are achieved, which founds a new landmark for the high arch dam construction in China.