Jansen Imke, Crielaard Hanneke, Wissing Tamar, Bouten Carlijn, Gijsen Frank, Akyildiz Ali C, Farrell Eric, van der Heiden Kim
Department of Biomedical Engineering, Thorax Center Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
APL Bioeng. 2023 Sep 29;7(3):036120. doi: 10.1063/5.0168087. eCollection 2023 Sep.
Rupture of the cap of an atherosclerotic plaque can lead to thrombotic cardiovascular events. It has been suggested, through computational models, that the presence of microcalcifications in the atherosclerotic cap can increase the risk of cap rupture. However, the experimental confirmation of this hypothesis is still lacking. In this study, we have developed a novel tissue-engineered model to mimic the atherosclerotic fibrous cap with microcalcifications and assess the impact of microcalcifications on cap mechanics. First, human carotid plaque caps were analyzed to determine the distribution, size, and density of microcalcifications in real cap tissue. Hydroxyapatite particles with features similar to real cap microcalcifications were used as microcalcification mimics. Injected clusters of hydroxyapatite particles were embedded in a fibrin gel seeded with human myofibroblasts which deposited a native-like collagenous matrix around the particles, during the 21-day culture period. Second harmonic multiphoton microscopy imaging revealed higher local collagen fiber dispersion in regions of hydroxyapatite clusters. Tissue-engineered caps with hydroxyapatite particles demonstrated lower stiffness and ultimate tensile stress than the control group samples under uniaxial tensile loading, suggesting increased rupture risk in atherosclerotic plaques with microcalcifications. This model supports previous computational findings regarding a detrimental role for microcalcifications in cap rupture risk and can further be deployed to elucidate tissue mechanics in pathologies with calcifying soft tissues.
动脉粥样硬化斑块帽的破裂可导致血栓形成性心血管事件。通过计算模型表明，动脉粥样硬化斑块帽中微钙化的存在会增加斑块帽破裂的风险。然而，这一假设仍缺乏实验证实。在本研究中，我们开发了一种新型组织工程模型，以模拟带有微钙化的动脉粥样硬化纤维帽，并评估微钙化对帽力学性能的影响。首先，分析人类颈动脉斑块帽，以确定真实帽组织中微钙化的分布、大小和密度。具有与真实帽微钙化相似特征的羟基磷灰石颗粒被用作微钙化模拟物。在21天的培养期内，将注射的羟基磷灰石颗粒簇嵌入接种了人肌成纤维细胞的纤维蛋白凝胶中，这些细胞在颗粒周围沉积了类似天然的胶原基质。二次谐波多光子显微镜成像显示，羟基磷灰石簇区域的局部胶原纤维分散度更高。在单轴拉伸载荷下，带有羟基磷灰石颗粒的组织工程帽的刚度和极限拉伸应力低于对照组样本，这表明有微钙化的动脉粥样硬化斑块破裂风险增加。该模型支持了先前关于微钙化在斑块帽破裂风险中起有害作用的计算结果，并且可以进一步用于阐明钙化软组织病变中的组织力学。
