Ramanujam Ranjini K, Maksudov Farkhad, Risman Rebecca A, Litvinov Rustem I, Weisel John W, Bassani John L, Barsegov Valeri, Purohit Prashant K, Tutwiler Valerie
Department of Biomedical Engineering, Rutgers University, NJ, USA.
Department of Chemistry, University of Massachusetts Lowell, MA, USA.
Acta Biomater. 2024 Dec;190:329-343. doi: 10.1016/j.actbio.2024.10.004. Epub 2024 Oct 10.
Embolization is a leading cause of mortality, yet we know little about clot rupture mechanics. Fibrin provides the main structural and mechanical stability to blood clots. Previous studies have shown that altering the concentration of coagulation activators (thrombin or tissue factor (TF)) has a significant impact on fibrin structure and viscoelastic properties, but their effects on rupture properties are mostly unknown. Toughness, which corresponds to the ability to resist rupture, is independent of viscoelastic properties. We used varying TF concentrations to alter the structure and toughness of human plasma clots. We performed single-edge notch rupture tests to examine fibrin toughness under a constant strain rate and we assessed viscoelastic mechanics using rheology. We utilized fluorescent confocal and scanning electron microscopy (SEM) to quantify the fibrin network structure under varying TF concentrations. Our results revealed that increased TF concentration resulted in increased number of fibrin fibers with a reduction in network pore size, thinner and shorter fibrin fibers. Increasing TF concentration yielded a maximum toughness at mid-TF concentration, such that fibrin diameter and number of fibers underlie a complex role in influencing the rupture resistance of blood clots, resulting in a nonmonotonic relationship between TF and toughness. A simple mechanical model, built on our findings from our Fluctuating Spring (FS) computational model, adopted to estimate the fracture toughness (critical energy release rate) as a function of TF predicts trends that are in good agreement with experiments. The differences in mechanical responses point to the importance of studying the structure-function relationships of fibrin networks, which may be predictive of the tendency for embolization. STATEMENT OF SIGNIFICANCE: Fibrin, a naturally occurring biomaterial, is the main mechanical and structural scaffold of blood clots that provides the necessary strength and stability to the clot, ensuring effective stemming of bleeding. The rupture of blood clots can result in the blockage of downstream vessels thereby blocking blood flow and oxygen supply. The fibrin network structure has been shown to influence the viscoelastic mechanical properties of clots, but has not been explored for fracture mechanics. Here, we modulate the fibrin network structure by varying the concentration of Tissue Factor (TF). Interestingly, the association between TF concentration and maximum toughness of the clots is non-monotonic. The variations in mechanical responses highlight the importance of studying the structure-function relationships of fibrin networks, as these may predict the tendency for embolization.
栓塞是导致死亡的主要原因之一，但我们对血凝块破裂机制知之甚少。纤维蛋白为血凝块提供了主要的结构和机械稳定性。先前的研究表明，改变凝血激活剂（凝血酶或组织因子（TF））的浓度会对纤维蛋白结构和粘弹性产生重大影响，但其对破裂特性的影响大多未知。韧性对应于抵抗破裂的能力，与粘弹性无关。我们使用不同的TF浓度来改变人血浆凝块的结构和韧性。我们进行了单边切口破裂试验，以在恒定应变率下检查纤维蛋白韧性，并使用流变学评估粘弹性力学。我们利用荧光共聚焦显微镜和扫描电子显微镜（SEM）来量化不同TF浓度下的纤维蛋白网络结构。我们的结果表明，TF浓度增加导致纤维蛋白纤维数量增加，网络孔径减小，纤维蛋白纤维更细、更短。增加TF浓度在中等TF浓度时产生最大韧性，因此纤维蛋白直径和纤维数量在影响血凝块抗破裂性方面起着复杂的作用，导致TF与韧性之间呈非单调关系。基于我们波动弹簧（FS）计算模型的研究结果构建的一个简单力学模型，用于估计作为TF函数的断裂韧性（临界能量释放率），其预测趋势与实验结果高度吻合。力学响应的差异表明研究纤维蛋白网络结构 - 功能关系的重要性，这可能预示着栓塞的倾向。
纤维蛋白是一种天然存在的生物材料，是血凝块的主要机械和结构支架，为血凝块提供必要的强度和稳定性，确保有效止血。血凝块破裂可导致下游血管阻塞，从而阻断血流和氧气供应。纤维蛋白网络结构已被证明会影响血凝块的粘弹性力学性能，但尚未对断裂力学进行研究。在这里，我们通过改变组织因子（TF）的浓度来调节纤维蛋白网络结构。有趣的是，TF浓度与血凝块最大韧性之间的关联是非单调的。力学响应的变化突出了研究纤维蛋白网络结构 - 功能关系的重要性，因为这些关系可能预示着栓塞的倾向。
