Laboratory of Biological Structure Mechanics (LaBS), Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy.
Division of Biomedical Engineering, University of Glasgow, Glasgow, UK.
Comput Methods Programs Biomed. 2023 Nov;241:107739. doi: 10.1016/j.cmpb.2023.107739. Epub 2023 Aug 1.
In-stent restenosis (ISR) following percutaneous coronary intervention with drug-eluting stent (DES) implantation remains an unresolved issue, with ISR rates up to 10%. The use of antiproliferative drugs on DESs has significantly reduced ISR. However, a complete knowledge of the mechanobiological processes underlying ISR is still lacking. Multiscale agent-based modelling frameworks, integrating continuum- and agent-based approaches, have recently emerged as promising tools to decipher the mechanobiological events driving ISR at different spatiotemporal scales. However, the integration of sophisticated drug models with an agent-based model (ABM) of ISR has been under-investigated. The aim of the present study was to develop a novel multiscale agent-based modelling framework of ISR following DES implantation.
The framework consisted of two bi-directionally coupled modules, namely (i) a drug transport module, simulating drug transport through a continuum-based approach, and (ii) a tissue remodelling module, simulating cellular dynamics through an ABM. Receptor saturation (RS), defined as the fraction of target receptors saturated with drug, is used to mediate cellular activities in the ABM, since RS is widely regarded as a measure of drug efficacy. Three studies were performed to investigate different scenarios in terms of drug mass (DM), drug release profiles (RP), coupling schemes and idealized vs. patient-specific artery geometries.
The studies demonstrated the versatility of the framework and enabled exploration of the sensitivity to different settings, coupling modalities and geometries. As expected, changes in the DM, RP and coupling schemes illustrated a variation in RS over time, in turn affecting the ABM response. For example, combined small DM - fast RP led to similar ISR degrees as high DM - moderate RP (lumen area reduction of ∼13/17% vs. ∼30% without drug). The use of a patient-specific geometry with non-equally distributed struts resulted in a heterogeneous RS map, but did not remarkably impact the ABM response.
The application to a patient-specific geometry highlights the potential of the framework to address complex realistic scenarios and lays the foundations for future research, including calibration and validation on patient datasets and the investigation of the effects of different plaque composition on the arterial response to DES.
药物洗脱支架（DES）经皮冠状动脉介入治疗后的支架内再狭窄（ISR）仍然是一个未解决的问题，ISR 发生率高达 10%。DES 上使用抗增殖药物显著降低了 ISR。然而，我们对导致 ISR 的机械生物学过程的全面认识仍然缺乏。多尺度基于代理的建模框架，将连续体和基于代理的方法结合在一起，最近已成为破译不同时空尺度下驱动 ISR 的机械生物学事件的有前途的工具。然而，将复杂的药物模型与基于代理的 ISR 模型（ABM）相结合的研究还很少。本研究的目的是开发一种新的 DES 植入后 ISR 的多尺度基于代理的建模框架。
该框架由两个双向耦合模块组成，即（i）药物输送模块，通过连续体方法模拟药物输送，和（ii）组织重塑模块，通过 ABM 模拟细胞动力学。受体饱和度（RS）用于介导 ABM 中的细胞活动，定义为与药物饱和的靶受体的分数，因为 RS 被广泛认为是药物疗效的度量。进行了三项研究，以调查药物质量（DM）、药物释放曲线（RP）、耦合方案以及理想化和患者特异性动脉几何形状方面的不同情况。
这些研究展示了该框架的多功能性，并能够探索不同设置、耦合模式和几何形状的敏感性。正如预期的那样，DM、RP 和耦合方案的变化说明了 RS 随时间的变化，进而影响 ABM 的反应。例如，小 DM - 快速 RP 的组合导致与高 DM - 适度 RP 相似的 ISR 程度（无药物时约 13/17%与 30%的管腔面积减少）。使用具有非均匀分布支架的患者特异性几何形状导致 RS 图的不均匀性，但对 ABM 的反应没有显著影响。
该框架在患者特异性几何形状上的应用突出了该框架解决复杂现实场景的潜力，并为未来的研究奠定了基础，包括在患者数据集上进行校准和验证，以及研究不同斑块组成对动脉对 DES 反应的影响。
