Heterogeneity Profoundly Alters Emergent Stress Fields in Constrained Multicellular Systems.

Stress fields emerging from the transfer of forces between cells within multicellular systems are increasingly being recognized as major determinants of cell fate. Current analytical and numerical models used for the calculation of stresses within cell monolayers assume homogeneous contractile and mechanical cellular properties; however, cell behavior varies by region within constrained tissues. Here, we show the impact of heterogeneous cell properties on resulting stress fields that guide cell phenotype and apoptosis. Using circular micropatterns, we measured biophysical metrics associated with cell mechanical stresses. We then computed cell-layer stress distributions using finite element contraction models and monolayer stress microscopy. In agreement with previous studies, cell spread area, alignment, and traction forces increase, whereas apoptotic activity decreases, from the center of cell layers to the edge. The distribution of these metrics clearly indicates low cell stress in central regions and high cell stress at the periphery of the patterns. However, the opposite trend is predicted by computational models when homogeneous contractile and mechanical properties are assumed. In our model, utilizing heterogeneous cell-layer contractility and elastic moduli values based on experimentally measured biophysical parameters, we calculate low cell stress in central areas and high anisotropic stresses in peripheral regions, consistent with the biometrics. These results clearly demonstrate that common assumptions of uniformity in cell contractility and stiffness break down in postconfluence confined multicellular systems. This work highlights the importance of incorporating regional variations in cell mechanical properties when estimating emergent stress fields from collective cell behavior.

Knot integrity using different suture types and different knot-tying techniques for reconstructive pelvic floor procedures.

INTRODUCTION AND HYPOTHESIS: Surgeons use a variety of sutures and knot-tying methods during pelvic reconstructive procedures. We hypothesized that knot-strength integrity will be similar with regards to type of knot, type of suture, and the knot-tying process. METHODS: Using six different suture materials, flat square knots and slip knots were tied robotically and by hand by two surgeons. Knot integrity was evaluated using an Instron 5544 machine. We measured force and elongation at suture failure or knot slippage (whichever came first) as well as force at 3-mm displacement. RESULTS: Four hundred and thirty-two knots were tie; one unraveled before the analysis, and 431 were tested. Three hundred and ninety-two knots reached or surpassed tensile strength of 30 N, the force at which tissue itself will fail. Knots tied with polyglyconate suture achieved the greatest tensile strength and those with OO-polydioxanone had the lowest. Hand-tied knots, regardless of technique and suture material, had greater tensile strength but greater elongation than robotically tied knots. Slip knots and flat square knots have similar integrity regardless of the tying technique. CONCLUSION: Hand-tied knots had greater tensile strength than robotic knots, but the strength to break all knots required supraphysiological conditions. The decision to use a specific type of suture based on strength is not supported by our results, suggesting that surgeons may choose sutures based on other characteristics and personal comfort.

Stiffness Properties of Adventitia, Media, and Full Thickness Human Atherosclerotic Carotid Arteries in the Axial and Circumferential Directions.

Arteries can be considered as layered composite material. Experimental data on the stiffness of human atherosclerotic carotid arteries and their media and adventitia layers are very limited. This study used uniaxial tests to determine the stiffness (tangent modulus) of human carotid artery sections containing American Heart Association type II and III lesions. Axial and circumferential oriented adventitia, media, and full thickness specimens were prepared from six human carotid arteries (total tissue strips: 71). Each artery yielded 12 specimens with two specimens in each of the following six categories; axial full thickness, axial adventitia (AA), axial media (AM), circumferential full thickness, circumferential adventitia (CA), and circumferential media (CM). Uniaxial testing was performed using Inspec 2200 controlled by software developed using labview. The mean stiffness of the adventitia was 3570 ± 667 and 2960 ± 331 kPa in the axial and circumferential directions, respectively, while the corresponding values for the media were 1070 ± 186 and 1800 ± 384 kPa. The adventitia was significantly stiffer than the media in both the axial (p = 0.003) and circumferential (p = 0.010) directions. The stiffness of the full thickness specimens was nearly identical in the axial (1540 ± 186) and circumferential (1530 ± 389 kPa) directions. The differences in axial and circumferential stiffness of media and adventitia were not statistically significant.

Morphological and Stress Vulnerability Indices for Human Coronary Plaques and Their Correlations with Cap Thickness and Lipid Percent: An IVUS-Based Fluid-Structure Interaction Multi-patient Study.

Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to quantify due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced as alternatives to obtain quantitative vulnerability assessment. Correlations between these indices and key plaque features were investigated. In vivo intravascular ultrasound (IVUS) data were acquired from 14 patients and IVUS-based 3D fluid-structure interaction (FSI) coronary plaque models with cyclic bending were constructed to obtain plaque wall stress/strain and flow shear stress for analysis. For the 617 slices from the 14 patients, lipid percentage, min cap thickness, critical plaque wall stress (CPWS), strain (CPWSn) and flow shear stress (CFSS) were recorded, and cap index, lipid index and morphological index were assigned to each slice using methods consistent with American Heart Association (AHA) plaque classification schemes. A stress index was introduced based on CPWS. Linear Mixed-Effects (LME) models were used to analyze the correlations between the mechanical and morphological indices and key morphological factors associated with plaque rupture. Our results indicated that for all 617 slices, CPWS correlated with min cap thickness, cap index, morphological index with r = -0.6414, 0.7852, and 0.7411 respectively (p<0.0001). The correlation between CPWS and lipid percentage, lipid index were weaker (r = 0.2445, r = 0.2338, p<0.0001). Stress index correlated with cap index, lipid index, morphological index positively with r = 0.8185, 0.3067, and 0.7715, respectively, all with p<0.0001. For all 617 slices, the stress index has 66.77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when both indices were jointly used with further validations from clinical studies.

Problem-Based Learning in Biomechanics: Advantages, Challenges, and Implementation Strategies.

Problem-based learning (PBL) has been shown to be effective in biomedical engineering education, particularly in motivating student learning, increasing knowledge retention, and developing problem solving, communication, and teamwork skills. However, PBL adoption remains limited by real challenges in effective implementation. In this paper, we review the literature on advantages and challenges of PBL and present our own experiences. We also provide practical guidelines for implementing PBL, including two examples of PBL modules from biomechanics courses at two different institutions. Overall, we conclude that the benefits for both professors and students support the use of PBL in biomedical engineering education.

Fiber Network Models Predict Enhanced Cell Mechanosensing on Fibrous Gels.

The propagation of mechanical signals through nonlinear fibrous tissues is much more extensive than through continuous synthetic hydrogels. Results from recent studies indicate that increased mechanical propagation arises from the fibrous nature of the material rather than the strain-stiffening property. The relative importance of different parameters of the fibrous network structure to this propagation, however, remains unclear. In this work, we directly compared the mechanical response of substrates of varying thickness subjected to a constant cell traction force using either a nonfibrous strain-stiffening continuum-based model or a volume-averaged fiber network model consisting of two different types of fiber network structures: one with low fiber connectivity (growth networks) and one with high fiber connectivity (Delaunay networks). The growth network fiber models predicted a greater propagation of substrate displacements through the model and a greater sensitivity to gel thickness compared to the more connected Delaunay networks and the nonlinear continuum model. Detailed analysis of the results indicates that rotational freedom of the fibers in a network with low fiber connectivity is critically important for enhanced, long-range mechanosensing. Our findings demonstrate the utility of multiscale models in predicting cells mechanosensing on fibrous gels, and they provide a more complete understanding of how cell traction forces propagate through fibrous tissues, which has implications for the design of engineered tissues and the stem cell niche.

The effect of substrate stiffness, thickness, and cross-linking density on osteogenic cell behavior.

Osteogenic cells respond to mechanical changes in their environment by altering their spread area, morphology, and gene expression profile. In particular, the bulk modulus of the substrate, as well as its microstructure and thickness, can substantially alter the local stiffness experienced by the cell. Although bone tissue regeneration strategies involve culture of bone cells on various biomaterial scaffolds, which are often cross-linked to enhance their physical integrity, it is difficult to ascertain and compare the local stiffness experienced by cells cultured on different biomaterials. In this study, we seek to characterize the local stiffness at the cellular level for MC3T3-E1 cells plated on biomaterial substrates of varying modulus, thickness, and cross-linking concentration. Cells were cultured on flat and wedge-shaped gels made from polyacrylamide or cross-linked collagen. The cross-linking density of the collagen gels was varied to investigate the effect of fiber cross-linking in conjunction with substrate thickness. Cell spread area was used as a measure of osteogenic differentiation. Finite element simulations were used to examine the effects of fiber cross-linking and substrate thickness on the resistance of the gel to cellular forces, corresponding to the equivalent shear stiffness for the gel structure in the region directly surrounding the cell. The results of this study show that MC3T3 cells cultured on a soft fibrous substrate attain the same spread cell area as those cultured on a much higher modulus, but nonfibrous substrate. Finite element simulations predict that a dramatic increase in the equivalent shear stiffness of fibrous collagen gels occurs as cross-linking density is increased, with equivalent stiffness also increasing as gel thickness is decreased. These results provide an insight into the response of osteogenic cells to individual substrate parameters and have the potential to inform future bone tissue regeneration strategies that can optimize the equivalent stiffness experienced by a cell.

A generalized method for the analysis of planar biaxial mechanical data using tethered testing configurations.

Simulation of the mechanical behavior of soft tissues is critical for many physiological and medical device applications. Accurate mechanical test data is crucial for both obtaining the form and robust parameter determination of the constitutive model. For incompressible soft tissues that are either membranes or thin sections, planar biaxial mechanical testing configurations can provide much information about the anisotropic stress-strain behavior. However, the analysis of soft biological tissue planar biaxial mechanical test data can be complicated by in-plane shear, tissue heterogeneities, and inelastic changes in specimen geometry that commonly occur during testing. These inelastic effects, without appropriate corrections, alter the stress-traction mapping and violates equilibrium so that the stress tensor is incorrectly determined. To overcome these problems, we presented an analytical method to determine the Cauchy stress tensor from the experimentally derived tractions for tethered testing configurations. We accounted for the measured testing geometry and compensate for run-time inelastic effects by enforcing equilibrium using small rigid body rotations. To evaluate the effectiveness of our method, we simulated complete planar biaxial test configurations that incorporated actual device mechanisms, specimen geometry, and heterogeneous tissue fibrous structure using a finite element (FE) model. We determined that our method corrected the errors in the equilibrium of momentum and correctly estimated the Cauchy stress tensor. We also noted that since stress is applied primarily over a subregion bounded by the tethers, an adjustment to the effective specimen dimensions is required to correct the magnitude of the stresses. Simulations of various tether placements demonstrated that typical tether placements used in the current experimental setups will produce accurate stress tensor estimates. Overall, our method provides an improved and relatively straightforward method of calculating the resulting stresses for planar biaxial experiments for tethered configurations, which is especially useful for specimens that undergo large shear and exhibit substantial inelastic effects.

Developing Porous Fibrin Scaffolds with Tunable Anisotropic Features to Direct Myoblast Orientation.

Functional regeneration of anisotropically aligned tissues such as ligaments, microvascular networks, myocardium, or skeletal muscle requires a temporal and spatial series of biochemical and biophysical cues to direct cell functions that promote native tissue regeneration. When these cues are lost during traumatic injuries such as volumetric muscle loss (VML), scar formation occurs, limiting the regenerative capacity of the tissue. Currently, autologous tissue transfer is the gold standard for treating injuries such as VML but can result in adverse outcomes including graft failure, donor site morbidity, and excessive scarring. Tissue-engineered scaffolds composed of biomaterials, cells, or both have been investigated to promote functional tissue regeneration but are still limited by inadequate tissue ingrowth. These scaffolds should provide precisely tuned topographies and stiffnesses using proregenerative materials to encourage tissue-specific functions such as myoblast orientation, followed by aligned myotube formation and recovery of functional contraction. In this study, we describe the design and characterization of novel porous fibrin scaffolds with anisotropic microarchitectural features that recapitulate the native tissue microenvironment and offer a promising approach for regeneration of aligned tissues. We used directional freeze-casting with varied fibrin concentrations and freezing temperatures to produce scaffolds with tunable degrees of anisotropy and strut widths. Nanoindentation analyses showed that the moduli of our fibrin scaffolds varied as a function of fibrin concentration and were consistent with native skeletal muscle tissue. Quantitative morphometric analyses of myoblast cytoskeletons on scaffold microarchitectures demonstrated enhanced cell alignment as a function of microarchitectural morphology. The ability to precisely control the anisotropic features of fibrin scaffolds promises to provide a powerful tool for directing aligned tissue ingrowth and enhance functional regeneration of tissues such as skeletal muscle.

Nonlinear strain stiffening is not sufficient to explain how far cells can feel on fibrous protein gels.

Recent observations suggest that cells on fibrous extracellular matrix materials sense mechanical signals over much larger distances than they do on linearly elastic synthetic materials. In this work, we systematically investigate the distance fibroblasts can sense a rigid boundary through fibrous gels by quantifying the spread areas of human lung fibroblasts and 3T3 fibroblasts cultured on sloped collagen and fibrin gels. The cell areas gradually decrease as gel thickness increases from 0 to 150 µm, with characteristic sensing distances of >65 µm below fibrin and collagen gels, and spreading affected on gels as thick as 150 µm. These results demonstrate that fibroblasts sense deeper into collagen and fibrin gels than they do into polyacrylamide gels, with the latter exhibiting characteristic sensing distances of <5 µm. We apply finite-element analysis to explore the role of strain stiffening, a characteristic mechanical property of collagen and fibrin that is not observed in polyacrylamide, in facilitating mechanosensing over long distances. Our analysis shows that the effective stiffness of both linear and nonlinear materials sharply increases once the thickness is reduced below 5 µm, with only a slight enhancement in sensitivity to depth for the nonlinear material at very low thickness and high applied traction. Multiscale simulations with a simplified geometry predict changes in fiber alignment deep into the gel and a large increase in effective stiffness with a decrease in substrate thickness that is not predicted by nonlinear elasticity. These results suggest that the observed cell-spreading response to gel thickness is not explained by the nonlinear strain-stiffening behavior of the material alone and is likely due to the fibrous nature of the proteins.

A Multiphysics Modeling Approach to Develop Right Ventricle Pulmonary Valve Replacement Surgical Procedures with a Contracting Band to Improve Ventricle Ejection Fraction.

Patients with repaired tetralogy of Fallot account for the majority of cases with late onset right ventricle (RV) failure. A new surgical procedure placing an elastic band in the right ventricle is proposed to improve RV function measured by ejection fraction. A multiphysics modeling approach is developed to combine cardiac magnetic resonance imaging, modeling, tissue engineering and mechanical testing to demonstrate feasibility of the new surgical procedure. Our modeling results indicated that the new surgical procedure has the potential to improve right ventricle ejection fraction by 2-7% which compared favorably with recently published drug trials to treat LV heart failure.

The Role of Apoptosis and Oxidative Stress in a Cell Spheroid Model of Calcific Aortic Valve Disease.

Calcific aortic valve disease (CAVD) is the most common heart valve disease among aging populations. There are two reported pathways of CAVD: osteogenic and dystrophic, the latter being more prevalent. Current two-dimensional (2D) in vitro CAVD models have shed light on the disease but lack three-dimensional (3D) cell-ECM interactions, and current 3D models require osteogenic media to induce calcification. The goal of this work is to develop a 3D dystrophic calcification model. We hypothesize that, as with 2D cell-based CAVD models, programmed cell death (apoptosis) is integral to calcification. We model the cell aggregation observed in CAVD by creating porcine valvular interstitial cell spheroids in agarose microwells. Upon culture in complete growth media (DMEM with serum), calcium nodules form in the spheroids within a few days. Inhibiting apoptosis with Z-VAD significantly reduced calcification, indicating that the calcification observed in this model is dystrophic rather than osteogenic. To determine the relative roles of oxidative stress and extracellular matrix (ECM) production in the induction of apoptosis and subsequent calcification, the media was supplemented with antioxidants with differing effects on ECM formation (ascorbic acid (AA), Trolox, or Methionine). All three antioxidants significantly reduced calcification as measured by Von Kossa staining, with the percentages of calcification per area of AA, Trolox, Methionine, and the non-antioxidant-treated control on day 7 equaling 0.17%, 2.5%, 6.0%, and 7.7%, respectively. As ZVAD and AA almost entirely inhibit calcification, apoptosis does not appear to be caused by a lack of diffusion of oxygen and metabolites within the small spheroids. Further, the observation that AA treatment reduces calcification significantly more than the other antioxidants indicates that the ECM stimulatory effect of AA plays a role inhibiting apoptosis and calcification in the spheroids. We conclude that, in this 3D in vitro model, both oxidative stress and ECM production play crucial roles in dystrophic calcification and may be viable therapeutic targets for preventing CAVD.

Quantification of patient-specific coronary material properties and their correlations with plaque morphological characteristics: An in vivo IVUS study.

BACKGROUND: A method using in vivo Cine IVUS and VH-IVUS data has been proposed to quantify material properties of coronary plaques. However, correlations between plaque morphological characteristics and mechanical properties have not been studied in vivo. METHOD: In vivo Cine IVUS and VH-IVUS data were acquired at 32 plaque cross-sections from 19 patients. Six morphological factors were extracted for each plaque. These samples were categorized into healthy vessel, fibrous plaque, lipid-rich plaque and calcified plaque for comparisons. Three-dimensional thin-slice models were constructed using VH-IVUS data to quantify in vivo plaque material properties following a finite element updating approach by matching Cine IVUS data. Effective Young's moduli were calculated to represent plaque stiffness for easy comparison. Spearman's rank correlation analysis was performed to identify correlations between plaque stiffness and morphological factor. Kruskal-Wallis test with Bonferroni correction was used to determine whether significant differences in plaque stiffness exist among four plaque groups. RESULT: Our results show that lumen circumference change has a significantly negative correlation with plaque stiffness (r = -0.7807, p = 0.0001). Plaque burden and calcification percent also had significant positive correlations with plaque stiffness (r = 0.5105, p < 0.0272 and r = 0.5312, p < 0.0193) respectively. Among the four categorized groups, calcified plaques had highest stiffness while healthy segments had the lowest. CONCLUSION: There is a close link between plaque morphological characteristics and mechanical properties in vivo. Plaque stiffness tends to be higher as coronary atherosclerosis advances, indicating the potential to assess plaque mechanical properties in vivo based on plaque compositions.

Anisotropy profoundly alters stress fields within contractile cells and cell aggregates.

Many biological phenomena such as cell proliferation and death are correlated with stress fields within cells. Stress fields are quantified using computational methods which rely on fundamental assumptions about local mechanical properties. Most existing methods such as Monolayer Stress Microscopy assume isotropic properties, yet experimental observations strongly suggest anisotropy. We first model anisotropy in circular cells analytically using Eshelby's inclusion method. Our solution reveals that uniform anisotropy cannot exist in cells due to the occurrence of substantial stress concentration in the central region. A more realistic non-uniform anisotropy model is then introduced based on experimental observations and implemented numerically which interestingly clears out stress concentration. Stresses within the entire aggregate also drastically change compared to the isotropic case, resulting in better agreement with observed biomarkers. We provide a physics-based mechanism to explain the low alignment of stress fibers in the center of cells, which might explain certain biological phenomena e.g., existence of disrupted rounded cells, and higher apoptosis rate at the center of circular aggregates.

Engineered vascular tissue fabricated from aggregated smooth muscle cells.

The goal of this study was to develop a system to rapidly generate engineered tissue constructs from aggregated cells and cell-derived extracellular matrix (ECM) to enable evaluation of cell-derived tissue structure and function. Rat aortic smooth muscle cells seeded into annular agarose wells (2, 4 or 6 mm inside diameter) aggregated and formed thick tissue rings within 2 weeks of static culture (0.76 mm at 8 days; 0.94 mm at 14 days). Overall, cells appeared healthy and surrounded by ECM comprised of glycosoaminoglycans and collagen, although signs of necrosis were observed near the centers of the thickest rings. Tissue ring strength and stiffness values were superior to those reported for engineered tissue constructs cultured for comparable times. The strength (100-500 kPa) and modulus (0.5-2 MPa) of tissue rings increased with ring size and decreased with culture duration. Finally, tissue rings cultured for 7 days on silicone mandrels fused to form tubular constructs. Ring margins were visible after 7 days, but tubes were cohesive and mechanically stable, and histological examination confirmed fusion between ring subunits. This unique system provides a versatile new tool for optimization and functional assessment of cell-derived tissue, and a new approach to creating tissue-engineered vascular grafts.

Mechanical Regulation of Apoptosis in the Cardiovascular System.

Apoptosis is a highly conserved physiological process of programmed cell death which is critical for proper organism development, tissue maintenance, and overall organism homeostasis. Proper regulation of cell removal is crucial, as both excessive and reduced apoptotic rates can lead to the onset of a variety of diseases. Apoptosis can be induced in cells in response to biochemical, electrical, and mechanical stimuli. Here, we review literature on specific mechanical stimuli that regulate apoptosis and the current understanding of how mechanotransduction plays a role in apoptotic signaling. We focus on how insufficient or excessive mechanical forces may induce apoptosis in the cardiovascular system and thus contribute to cardiovascular disease. Although studies have demonstrated that a broad range of mechanical stimuli initiate and/or potentiate apoptosis, they are predominantly correlative, and no mechanisms have been established. In this review, we attempt to establish a unifying mechanism for how various mechanical stimuli initiate a single cellular response, i.e. apoptosis. We hypothesize that the cytoskeleton plays a central role in this process as it does in determining myriad cell behaviors in response to mechanical inputs. We also describe potential approaches of using mechanomedicines to treat various diseases by altering apoptotic rates in specific cells. The goal of this review is to summarize the current state of the mechanobiology field and suggest potential avenues where future research can explore.

A Novel Pulmonary Valve Replacement Surgery Strategy Using Contracting Band for Patients With Repaired Tetralogy of Fallot: An MRI-Based Multipatient Modeling Study.

Patients with repaired Tetralogy of Fallot (ToF), a congenital heart defect which includes a ventricular septal defect and severe right ventricular outflow obstruction, account for the majority of cases with late-onset right ventricle (RV) failure. Current surgery procedures, including pulmonary valve replacement (PVR) with right ventricle remodeling, yield mixed results. PVR with active band insertion was hypothesized to be of clinical usage on improving RV function measured by ejection fraction (EF). In lieu of risky open-heart surgeries and experiments on animal and human, computational biomechanical models were adapted to study the impact of PVR with five band insertion options. Cardiac magnetic resonance (CMR) images were acquired from seven TOF patients before PVR surgery for model construction. For each patient, five different surgery plans combined with passive and active contraction band with contraction ratio of 20, 15, and 10% were studied. Those five plans include three single-band plans with different band locations; one plan with two bands, and one plan with three bands. Including the seven no-band models, 147 computational bi-ventricle models were constructed to simulate RV cardiac functions and identify optimal band plans. Patient variations with different band plans were investigated. Surgery plan with three active contraction bands and band active contraction ratio of 20% had the best performance on improving RV function. The mean ± SD RV ejection fraction value from the seven patients was 42.90 ± 5.68%, presenting a 4.19% absolute improvement or a 10.82% relative improvement, when compared with the baseline models (38.71 ± 5.73%, p = 0.016). The EF improvements from the seven patients varied from 2.87 to 6.01%. Surgical procedures using active contraction bands have great potential to improve RV function measured by ejection fraction for patients with repaired ToF. It is possible to have higher right ventricle ejection fraction improvement with more bands and higher band active contraction ratio. Our findings with computational models need to be further validated by animal experiments before clinical trial could become possible.

Quantifying Patient-Specific in vivo Coronary Plaque Material Properties for Accurate Stress/Strain Calculations: An IVUS-Based Multi-Patient Study.

Introduction: Mechanical forces are closely associated with plaque progression and rupture. Precise quantifications of biomechanical conditions using in vivo image-based computational models depend heavily on the accurate estimation of patient-specific plaque mechanical properties. Currently, mechanical experiments are commonly performed on ex vivo cardiovascular tissues to determine plaque material properties. Patient-specific in vivo coronary material properties are scarce in the existing literature. Methods: In vivo Cine intravascular ultrasound and virtual histology intravascular ultrasound (IVUS) slices were acquired at 20 plaque sites from 13 patients. A three-dimensional thin-slice structure-only model was constructed for each slice to obtain patient-specific in vivo material parameter values following an iterative scheme. Effective Young's modulus (YM) was calculated to indicate plaque stiffness for easy comparison purposes. IVUS-based 3D thin-slice models using in vivo and ex vivo material properties were constructed to investigate their impacts on plaque wall stress/strain (PWS/PWSn) calculations. Results: The average YM values in the axial and circumferential directions for the 20 plaque slices were 599.5 and 1,042.8 kPa, respectively, 36.1% lower than those from published ex vivo data. The YM values in the circumferential direction of the softest and stiffest plaques were 103.4 and 2,317.3 kPa, respectively. The relative difference of mean PWSn on lumen using the in vivo and ex vivo material properties could be as high as 431%, while the relative difference of mean PWS was much lower, about 3.07% on average. Conclusion: There is a large inter-patient and intra-patient variability in the in vivo plaque material properties. In vivo material properties have a great impact on plaque stress/strain calculations. In vivo plaque material properties have a greater impact on strain calculations. Large-scale-patient studies are needed to further verify our findings.

Using intravascular ultrasound image-based fluid-structure interaction models and machine learning methods to predict human coronary plaque vulnerability change.

Plaque vulnerability prediction is of great importance in cardiovascular research. In vivo follow-up intravascular ultrasound (IVUS) coronary plaque data were acquired from nine patients to construct fluid-structure interaction models to obtain plaque biomechanical conditions. Morphological plaque vulnerability index (MPVI) was defined to measure plaque vulnerability. The generalized linear mixed regression model (GLMM), support vector machine (SVM) and random forest (RF) were introduced to predict MPVI change (ΔMPVI = MPVIfollow-up‒MPVIbaseline) using ten risk factors at baseline. The combination of mean wall thickness, lumen area, plaque area, critical plaque wall stress, and MPVI was the best predictor using RF with the highest prediction accuracy 91.47%, compared to 90.78% from SVM, and 85.56% from GLMM. Machine learning method (RF) improved the prediction accuracy by 5.91% over that from GLMM. MPVI was the best single risk factor using both GLMM (82.09%) and RF (78.53%) while plaque area was the best using SVM (81.29%).