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.

Reducing retraction in engineered tissues through design of sequential growth factor treatment.

Heart valve disease is associated with high morbidity and mortality worldwide, resulting in hundreds of thousands of heart valve replacements each year. Tissue engineered heart valves (TEHVs) have the potential to overcome the major limitations of traditional replacement valves; however, leaflet retraction has led to the failure of TEHVs in preclinical studies. Sequentially varying growth factors over time has been utilized to promote maturation of engineered tissues and may be effective in reducing tissue retraction, yet it is difficult to predict the effects of such treatments due to complex interactions between the cells and the extracellular matrix (ECM), biochemical environment, and mechanical stimuli. We hypothesize that sequential treatments of fibroblast growth factor 2 (FGF-2) and transforming growth factor beta 1 (TGF-ß1) can be used to minimize cell-generated tissue retraction by decreasing active cell contractile forces exerted on the ECM and by inducing the cells to increase the ECM stiffness. Using a custom culturing and monitoring system for 3D tissue constructs, we designed and tested various TGF-ß1 and FGF-2 based growth factor treatments, and successfully reduced tissue retraction by 85% and increased the ECM elastic modulus by 260% compared to non-growth factor treated controls, without significantly increasing the contractile force. We also developed and verified a mathematical model to predict the effects of various temporal variations in growth factor treatments and analyzed relationships between tissue properties, the contractile forces, and retraction. These findings improve our understanding of growth factor-induced cell-ECM biomechanical interactions, which can inform the design of next generation TEHVs with reduced retraction. The mathematical models could also potentially be applied toward fast screening and optimizing growth factors for use in the treatment of diseases including fibrosis.

Multicellular aligned bands disrupt global collective cell behavior.

Mechanical stress patterns emerging from collective cell behavior have been shown to play critical roles in morphogenesis, tissue repair, and cancer metastasis. In our previous work, we constrained valvular interstitial cell (VIC) monolayers on circular protein islands to study emergent behavior in a controlled manner and demonstrated that the general patterns of cell alignment, size, and apoptosis correlate with predicted mechanical stress fields if radially increasing stiffness or contractility are used in the computational models. However, these radially symmetric models did not predict the existence of local regions of dense aligned cells observed in seemingly random locations of individual aggregates. The goal of this study is to determine how the heterogeneities in cell behavior emerge over time and diverge from the predicted collective cell behavior. Cell-cell interactions in circular multicellular aggregates of VICs were studied with time-lapse imaging ranging from hours to days, and migration, proliferation, and traction stresses were measured. Our results indicate that elongated cells create strong local alignment within preconfluent cell populations on the microcontact printed protein islands. These cells influence the alignment of additional cells to create dense, locally aligned bands of cells which disrupt the predicted global behavior. Cells are highly elongated at the endpoints of the bands yet have decreased spread area in the middle and reduced mobility. Although traction stresses at the endpoints of bands are enhanced, even to the point of detaching aggregates from the culture surface, the cells in dense bands exhibit reduced proliferation, less nuclear YAP, and increased apoptotic rates indicating a low stress environment. These findings suggest that strong local cell-cell interactions between primary fibroblastic cells can disrupt the global collective cellular behavior leading to substantial heterogeneity of cell behaviors in constrained monolayers. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues. STATEMENT OF SIGNIFICANCE: Mechanical stress patterns emerging from collective cell behavior play critical roles in morphogenesis, tissue repair, and cancer metastasis. Much has been learned of these collective behaviors by utilizing microcontact printing to constrain cell monolayers (aggregates) into specific shapes. Here we utilize these tools along with long-term video microscopy tracking of individual aggregates to determine how heterogeneous collective behaviors unique to primary fibroblastic cells emerge over time and diverge from computed stress fields. We find that dense multicellular bands form from local collective behavior and disrupt the global collective behavior resulting in heterogeneous patterns of migration, traction stresses, proliferation, and apoptosis. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues.

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.

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.

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.

Learning Environments and Evidence-Based Practices in Bioengineering and Biomedical Engineering.

This paper provides a synopsis of discussions related to the Learning Environments track of the Fourth BME Education Summit held at Case Western Reserve University in Cleveland, Ohio in May 2019. This summit was organized by the Council of Chairs of Bioengineering and Biomedical Engineering, and participants included over 300 faculty members from 100+ accredited undergraduate programs. The Learning Environments track had six interactive workshops that provided facilitated discussion and provide recommendations in the areas of: (1) Authentic project/problem identification in clinical, industrial, and global settings, (2) Experiential problem/project-based learning within courses, (3) Experiential learning in co-curricular learning settings, (4) Team-based learning, (5) Teaching to reach a diverse classroom, and (6) innovative platforms and pedagogy. A summary of the findings, best practices and recommendations from each of the workshops is provided under separate headings below, and a list of resources is provided at the end of this paper.

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.

Hyaluronic acid regulates heart valve interstitial cell contraction in fibrin-based scaffolds.

Heart valve disease is associated with high morbidity and mortality worldwide resulting in hundreds of thousands of heart valve replacements each year. Tissue engineered heart valves (TEHVs) have the potential to overcome the major limitations of traditional replacement valves; however, leaflet retraction has led to the failure of TEHVs in preclinical studies. As native unmodified hyaluronic acid (HA) is known to promote healthy tissue development in native heart valves, we hypothesize that adding unmodified HA to fibrin-based scaffolds common to tissue engineering will reduce retraction by increasing cell-scaffold interactions and density of the scaffolds. Using a custom high-throughput culture system, we found that incorporating HA into millimeter-scale fibrin-based cell-populated scaffolds increases initial fiber diameter and cell-scaffold interactions, causing a cascade of mechanical, morphological, and cellular responses. These changes lead to higher levels of scaffold compaction and stiffness, increased cell alignment, and less bundling of fibrin fibers by the cells during culture. These effects significantly reduce scaffold retraction and total contractile force each by around 25%. These findings increase our understanding of how HA alters tissue remodeling and could inform the design of the next generation of tissue engineered heart valves to help reduce retraction. STATEMENT OF SIGNIFICANCE: Tissue engineered heart valves (TEHVs) have the potential to overcome the major limitations of traditional replacement valves; however, leaflet retraction induced by excessive myofibroblast activation has led to failure in preclinical studies. Developing valves are rich in hyaluronic acid (HA), which helps maintain a physiological environment for tissue remodeling without retraction. We hypothesized that adding unmodified HA to TEHVs would reduce retraction by increasing cell-scaffold interactions and density of the scaffolds. Using a high-throughput tissue culture platform, we demonstrate that HA incorporation into a fibrin-based scaffold can significantly reduce tissue retraction and total contractile force by increasing fiber bundling and altering cell-mediated matrix remodeling, therefore increasing gel density and stiffness. These finding increase our knowledge of native HA's effects within the extracellular matrix, and provide a new tool for TEHV design.

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.

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.

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%).

Multi-Band Surgery for Repaired Tetralogy of Fallot Patients With Reduced Right Ventricle Ejection Fraction: A Pilot Study.

INTRODUCTION: Right ventricle (RV) failure is one of the most common symptoms among patients with repaired tetralogy of Fallot (TOF). The current surgery treatment approach including pulmonary valve replacement (PVR) showed mixed post-surgery outcomes. A novel PVR surgical strategy using active contracting bands is proposed to improve the post-PVR outcome. In lieu of testing the risky surgical procedures on real patients, computational simulations (virtual surgery) using biomechanical ventricle models based on patient-specific cardiac magnetic resonance (CMR) data were performed to test the feasibility of the PVR procedures with active contracting bands. Different band combination and insertion options were tested to identify optimal surgery designs. METHOD: Cardiac magnetic resonance data were obtained from one TOF patient (male, age 23) whose informed consent was obtained. A total of 21 finite element models were constructed and solved following our established procedures to investigate the outcomes of the band insertion surgery. The non-linear anisotropic Mooney-Rivlin model was used as the material model. Five different band insertion plans were simulated (three single band models with different band locations, one model with two bands, and one model with three bands). Three band contraction ratios (10, 15, and 20%) and passive bands (0% contraction ratio) were tested. RV ejection fraction was used as the measure for cardiac function. RESULTS: The RV ejection fraction from the three-band model with 20% contraction increased to 41.58% from the baseline of 37.38%, a 4.20% absolute improvement. The RV ejection fractions from the other four band models with 20% contraction rate were 39.70, 39.45, and 40.70% (two-band) and 39.17%, respectively. The mean RV stress and strain values from all of the 21 models showed only modest differences (5-11%). CONCLUSION: This pilot study demonstrated that the three-band model with 20% band contraction ratio led to 4.20% absolute improvement in the RV ejection fraction, which is considered as clinically significant. The passive elastic bands led to the reduction of the RV ejection fractions. The modeling results and surgical strategy need to be further developed and validated by a multi-patient study and animal experiments before clinical trial could become possible. Tissue regeneration techniques are needed to produce materials for the contracting bands.

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.

Ventricle stress/strain comparisons between Tetralogy of Fallot patients and healthy using models with different zero-load diastole and systole morphologies.

Patient-specific in vivo ventricle mechanical wall stress and strain conditions are important for cardiovascular investigations and should be calculated from correct zero-load ventricle morphologies. Cardiac magnetic resonance (CMR) data were obtained from 6 healthy volunteers and 12 Tetralogy of Fallot (TOF) patients with consent obtained. 3D patient-specific CMR-based ventricle models with different zero-load diastole and systole geometries due to myocardium contraction and relaxation were constructed to qualify right ventricle (RV) diastole and systole stress and strain values at begin-filling, end-filling, begin-ejection, and end-ejection, respectively. Our new models (called 2G models) can provide end-diastole and end-systole stress/strain values which models with one zero-load geometries (called 1G models) could not provide. 2G mean end-ejection stress value from the 18 participants was 321.4% higher than that from 1G models (p = 0.0002). 2G mean strain values was 230% higher than that of 1G models (p = 0.0002). TOF group (TG) end-ejection mean stress value was 105.4% higher than that of healthy group (HG) (17.54±7.42kPa vs. 8.54±0.92kPa, p = 0.0245). Worse outcome group (WG, n = 6) post pulmonary valve replacement (PVR) begin-ejection mean stress was 57.4% higher than that of better outcome group (BG, 86.94±26.29 vs. 52.93±22.86 kPa; p = 0.041). Among 7 selected parameters, End-filling stress was the best predictor to differentiate BG patients from WG patients with prediction accuracy = 0.8208 and area under receiver operating characteristic curve (AUC) value at 0.8135 (EE stress). Large scale studies are needed to further validate our findings.

Combining morphological and biomechanical factors for optimal carotid plaque progression prediction: An MRI-based follow-up study using 3D thin-layer models.

Plaque progression prediction is of fundamental significance to cardiovascular research and disease diagnosis, prevention, and treatment. Magnetic resonance image (MRI) data of carotid atherosclerotic plaques were acquired from 20 patients with consent obtained. 3D thin-layer models were constructed to calculate plaque stress and strain. Data for ten morphological and biomechanical risk factors were extracted for analysis. Wall thickness increase (WTI), plaque burden increase (PBI) and plaque area increase (PAI) were chosen as three measures for plaque progression. Generalized linear mixed models (GLMM) with 5-fold cross-validation strategy were used to calculate prediction accuracy and identify optimal predictor. The optimal predictor for PBI was the combination of lumen area (LA), plaque area (PA), lipid percent (LP), wall thickness (WT), maximum plaque wall stress (MPWS) and maximum plaque wall strain (MPWSn) with prediction accuracy = 1.4146 (area under the receiver operating characteristic curve (AUC) value is 0.7158), while PA, plaque burden (PB), WT, LP, minimum cap thickness, MPWS and MPWSn was the best for WTI (accuracy = 1.3140, AUC = 0.6552), and a combination of PA, PB, WT, MPWS, MPWSn and average plaque wall strain (APWSn) was the best for PAI with prediction accuracy = 1.3025 (AUC = 0.6657). The combinational predictors improved prediction accuracy by 9.95%, 4.01% and 1.96% over the best single predictors for PAI, PBI and WTI (AUC values improved by 9.78%, 9.45%, and 2.14%), respectively. This suggests that combining both morphological and biomechanical risk factors could lead to better patient screening strategies.

Patient-specific in vivo right ventricle material parameter estimation for patients with tetralogy of Fallot using MRI-based models with different zero-load diastole and systole morphologies.

Patient-specific in vivo ventricle material parameter determination is important for cardiovascular investigations. A new cardiac magnetic image (CMR)-based modeling approach with different zero-load diastole and systole geometries was adopted to estimate right ventricle material parameter values for healthy and patients with Tetralogy of Fallot (TOF) and seeking potential clinical applications. CMR data were obtained from 6 healthy volunteers and 16 TOF patients with consent obtained. CMR-based RV/LV models were constructed using two zero-load geometries (diastole and systole, 2G model). Material parameter values for begin-filling (BF), end-filling (EF), begin-ejection (BE), and end-ejection (EE) were recorded for analyses. Effective Young's moduli (YM) for fiber direction stress-strain curves were calculated for easy comparisons. The mean EE YM value of TOF patients was 78.6% higher than that of the healthy group (HG). The mean end-ejection YM value from worse-outcome TOF group (WG) post pulmonary valve replacement (PVR) surgery was 59.5% higher than that from the better-outcome TOF group (BG). Using begin-filling YM and end-ejection YM as predictors and the classic logistic regression model to different better-outcome group patients from worse-outcome group patients, the areas under Receiver Operating Characteristic (ROC) curves were found to be 0.797 and 0.883 for begin-filling YM and end-ejection YM, respectively. The sensitivity and specificity 0.761 and 0.755 using end-ejection YM as the predictor. This preliminary study suggests that ventricle material stiffness could be a potential parameter to be used to differentiate BG patients from WG patients with further effort and large-scale patient data validations.

Fluid-structure interaction models based on patient-specific IVUS at baseline and follow-up for prediction of coronary plaque progression by morphological and biomechanical factors: A preliminary study.

Plaque morphology and biomechanics are believed to be closely associated with plaque progression. In this paper, we test the hypothesis that integrating morphological and biomechanical risk factors would result in better predictive power for plaque progression prediction. A sample size of 374 intravascular ultrasound (IVUS) slices was obtained from 9 patients with IVUS follow-up data. 3D fluid-structure interaction models were constructed to obtain both structural stress/strain and fluid biomechanical conditions. Data for eight morphological and biomechanical risk factors were extracted for each slice. Plaque area increase (PAI) and wall thickness increase (WTI) were chosen as two measures for plaque progression. Progression measure and risk factors were fed to generalized linear mixed models and linear mixed-effect models to perform prediction and correlation analysis, respectively. All combinations of eight risk factors were exhausted to identify the optimal predictor(s) with highest prediction accuracy defined as sum of sensitivity and specificity. When using a single risk factor, plaque wall stress (PWS) at baseline was the best predictor for plaque progression (PAI and WTI). The optimal predictor among all possible combinations for PAI was PWS + PWSn + Lipid percent + Min cap thickness + Plaque Area (PA) + Plaque Burden (PB) (prediction accuracy = 1.5928) while Wall Thickness (WT) + Plaque Wall Strain (PWSn) + Plaque Area (PA) was the best for WTI (1.2589). This indicated that PAI was a more predictable measure than WTI. The combination including both morphological and biomechanical parameters had improved prediction accuracy, compared to predictions using only morphological features.

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.