Tissue-engineered collagenous fibrous cap models to systematically elucidate atherosclerotic plaque rupture

Abstract

A significant amount of vascular thrombotic events are associated with rupture of the fibrous cap that overlie atherosclerotic plaques. Cap rupture is however difficult to predict due to the heterogenous composition of the plaque, unknown material properties, and the stochastic nature of the event. Here, we aim to create tissue engineered human fibrous cap models with a variable but controllable collagen composition, suitable for mechanical testing, to scrutinize the reciprocal relationships between composition and mechanical properties. Myofibroblasts were cultured in 1 × 1.5 cm-sized fibrin-based constrained gels for 21 days according to established (dynamic) culture protocols (i.e. static, intermittent or continuous loading) to vary collagen composition (e.g. amount, type and organization). At day 7, a soft 2 mm ∅ fibrin inclusion was introduced in the centre of each tissue to mimic the soft lipid core, simulating the heterogeneity of a plaque. Results demonstrate reproducible collagenous tissues, that mimic the bulk mechanical properties of human caps and vary in collagen composition due to the presence of a successfully integrated soft inclusion and the culture protocol applied. The models can be deployed to assess tissue mechanics, evolution and failure of fibrous caps or complex heterogeneous tissues in general.

An Improved Understanding of the Pathophysiology of Pelvic Organ Prolapse: A 3D In Vitro Model under Static and Mechanical Loading Conditions

“…Moreover, we observe that I‐strain promotes collagen synthesis and alignment of the collagen fibers to the strain direction in both POP and non‐POP fibroblasts, which has been previously observed in 3D cultured endothelial cells. [ 32 ] The limited availability of studies investigating the effect of mechanical loading on these fibroblasts makes it difficult to compare our results to other findings. The few studies that investigated the effect of mechanical loading on both POP and non‐POP fibroblasts reported ambiguous results (Table S8, Supporting Information), [ 5,17,18,21–23 ] which is probably due to the differences in the mechanical load applied (e.g., different strain, duration, and frequency used).…”

“…The adjustments conducted on the Bioflex plate did not negatively affect the amount of applied strain (3.08 ± 0.98%), which is in line with a previous study that conducted similar adjustments. [32] Prior to mechanical loading, the 3D cultured fibroblasts were cultured for 14 days under static conditions to allow sufficient ECM deposition (Figure 4B-ii), which prevents rupture of the hydrogel during mechanical loading. Upon exposure to mechanical loading, the hydrogels exhibit compaction in the center, which is probably due to increased fibroblast contraction (Figure 4B-iii).…”

Vascular stiffening and endothelial dysfunction in atherosclerosis

“…The atherosclerotic plaque of mice differs considerably in its biomechanical composition compared to human plaques and is considered resistant to plaque rupture [ 71 ]. The use of tissue-engineered plaques to study the mechanical properties of human plaque could be an interesting alternative [ 72 ▪ ].…”

Shared decision‐making in the realm of uncertainty: The example of coronary artery disease through an EBM and complexity science lens

“…15 Another example is our incomplete understanding of the reasons for plaque rupture in coronary arteries. 16 Furthermore, the mechanistic reasoning frame, based on models and generalizations of body function, will not overcome the obvious problem of explaining the complexities arising from biological and interpersonal variability. This frame cannot take account of the fact that human bodies subtly differ in their biological blueprint, and that they differently adapt their function depending on social and environmental circumstances-not only as 'body machines' but especially as social beings with their personal ideas, values and expectations.…”

“…For example, our understanding of flow of liquids through branched arterial systems remains quite poor 15 . Another example is our incomplete understanding of the reasons for plaque rupture in coronary arteries 16 . Furthermore, the mechanistic reasoning frame, based on models and generalizations of body function, will not overcome the obvious problem of explaining the complexities arising from biological and interpersonal variability.…”