Integrating Cardiovascular Engineering and Biofluid Mechanics in High School Science, Technology, Engineering, and Mathematics Education: An Experiential Approach.

Science, technology, engineering, and mathematics (STEM) education workshops and programs play a key role in promoting early exposure to scientific applications and questions. Such early engagement leads to growing not only passion and interest in science, but it also leads to skill development through hands-on learning and critical thinking activities. Integrating physiology and engineering together is necessary especially to promote health technology awareness and introduce the young generation to areas where innovation is needed and where there is no separation between health-related matters and engineering methods and applications. To achieve this, we created a workshop aimed at K-12 (grades 9-11) students as part of the Summer Youth Programs at Michigan Technological University. The aim of this workshop was to expose students to how engineering concepts and methods translate into health- and medicine-related applications and cases. The program consisted of a total of 15 h and was divided into three sections over a period of 2 weeks. It involved a combination of theoretical and hands-on guided activities that we developed. At the end of the workshop, the students were provided a lesson or activity-specific assessment sheet and a whole workshop-specific assessment sheet to complete. They rated the programs along a 1-5 Likert scale and provided comments and feedback on what can be improved in the future. Students rated hands-on activities the highest in comparison with case studies and individual independent research. Conclusively, this STEM summer-youth program was a successful experience with many opportunities that will contribute to the continued improvement of the workshop in the future.

Mechanical and Structural Evaluation of Tricuspid Bicuspidization in a Porcine Model.

INTRODUCTION: Tricuspid regurgitation (TR) affects approximately 1.6 million Americans and is associated with just a 63.9% 1-year survival rate in its moderate to severe forms due to its asymptomatic nature and late diagnosis and surgical referral. As a result, industrial fervor has begun to broach this topic, with several percutaneous treatment devices currently under development. As much remains unknown about the tricuspid apparatus, the mechanics of these procedures remain unquantified. In this study, a testing apparatus and technique for the evaluation of percutaneous tricuspid valve (TV) bicuspidization were developed for the evaluation of these parameters in twelve porcine hearts. METHODS: The passive relaxed myocardial state and the active contracted state were each induced in six porcine hearts and the bicuspidization experiment was run twice, the second time after induction of TR. TV annular area, cinching force, static leakage through the TV annulus, and annular ellipticity were quantified and compared among the groups. RESULTS: The use of phenol was effective to induce functional TR by increased annular area. Cinching force was not found to differ between any of the testing states, but the bicuspidization experiment was able to reduce the TR annular area to that of its healthy counterpart in addition to reducing static leakage through the TV annulus. Despite appropriately reducing the area, bicuspidization was found to induce a more circular TV annular shape. CONCLUSION: Taken together, these results provide a first mechanical analysis of the TV bicuspidization mechanism and may serve as a point of reference for future clinical animal studies.

A multilayered valve leaflet promotes cell-laden collagen type I production and aortic valve hemodynamics.

Patients with aortic heart valve disease are limited to valve replacements that lack the ability to grow and remodel. This presents a major challenge for pediatric patients who require a valve capable of somatic growth and at a smaller size. A patient-specific heart valve capable of growth and remodeling while maintaining proper valve function would address this major issue. Here, we recreate the native valve leaflet structure composed of poly-ε-caprolactone (PCL) and cell-laden gelatin-methacrylate/poly (ethylene glycol) diacrylate (GelMA/PEGDA) hydrogels using 3D printing and molding, and then evaluate the ability of the multilayered scaffold to produce collagen matrix under physiological shear stress conditions. We also characterized the valve hemodynamics under aortic physiological flow conditions. The valve's fibrosa layer was replicated by 3D printing PCL in a circumferential direction similar to collagen alignment in the native leaflet, and GelMA/PEGDA sustained and promoted cell viability in the spongiosa/ventricularis layers. We found that collagen type I production can be increased in the multilayered scaffold when it is exposed to pulsatile shear stress conditions over static conditions. When the PCL component was mounted onto a valve ring and tested under physiological aortic valve conditions, the hemodynamics were comparable to commercially available valves. Our results demonstrate that a structurally representative valve leaflet can be generated using 3D printing and that the PCL layer of the leaflet can sustain proper valve function under physiological aortic valve conditions.

Cardiac wall mechanics analysis in hypertension-induced heart failure rats with preserved ejection fraction.

Although cardiac wall mechanics is of importance for understanding heart failure with preserved ejection fraction (HFpEF), there is a lack of relevant mechanics studies. The aim of this study was to analyze the changes in stress and strain in the left ventricle (LV) in hypertension-induced HFpEF rats. Based on experimental measurements in DSS rats fed with high-salt (HS) and low-salt (LS) diets, LV stress and strain were computed throughout the cardiac cycle using Continuity software. HS-feeding increased myofiber stress and strain along both the transmural and longitudinal directions at the end-diastolic state but resulted in a lower absolute value of strain and relatively unchanged stress at the end-systolic state. Moreover, the end-diastolic stress and strain decreased with increasing radial position from the endocardial towards the epicardial walls despite negligible changes along the longitudinal direction. The changes in LV wall mechanics characterized the elevated diastolic LV stiffness and slow LV relaxation in HS-fed rats of HFpEF. These findings denote that a vicious cycle of increased stress and strain and diastolic dysfunction can prompt the development of HFpEF.

Identification of in vivo nonlinear anisotropic mechanical properties of ascending thoracic aortic aneurysm from patient-specific CT scans.

Accurate identification of in vivo nonlinear, anisotropic mechanical properties of the aortic wall of individual patients remains to be one of the critical challenges in the field of cardiovascular biomechanics. Since only the physiologically loaded states of the aorta are given from in vivo clinical images, inverse approaches, which take into account of the unloaded configuration, are needed for in vivo material parameter identification. Existing inverse methods are computationally expensive, which take days to weeks to complete for a single patient, inhibiting fast feedback for clinicians. Moreover, the current inverse methods have only been evaluated using synthetic data. In this study, we improved our recently developed multi-resolution direct search (MRDS) approach and the computation time cost was reduced to 1~2 hours. Using the improved MRDS approach, we estimated in vivo aortic tissue elastic properties of two ascending thoracic aortic aneurysm (ATAA) patients from pre-operative gated CT scans. For comparison, corresponding surgically-resected aortic wall tissue samples were obtained and subjected to planar biaxial tests. Relatively close matches were achieved for the in vivo-identified and ex vivo-fitted stress-stretch responses. It is hoped that further development of this inverse approach can enable an accurate identification of the in vivo material parameters from in vivo image data.

Chameleon-Inspired Strain-Accommodating Smart Skin.

Stimuli-responsive color-changing hydrogels, commonly colored using embedded photonic crystals (PCs), have potential applications ranging from chemical sensing to camouflage and anti-counterfeiting. A major limitation in these PC hydrogels is that they require significant deformation (>20%) in order to change the PC lattice constant and generate an observable chromatic shift (∼100 nm). By analyzing the mechanism of how chameleon skin changes color, we developed a strain-accommodating smart skin (SASS), which maintains near-constant size during chromatic shifting. SASS is composed of two types of hydrogels: a stimuli-responsive, PC-containing hydrogel that is patterned within a second hydrogel with robust mechanical properties, which permits strain accommodation. In contrast to conventional "accordion"-type PC responsive hydrogels, SASS maintains near-constant volume during chromatic shifting. Importantly, SASS materials are stretchable (strain ∼150%), amenable to patterning, spectrally tunable, and responsive to both heat and natural sunlight. We demonstrate examples of using SASS for biomimicry. Our strategy, to embed responsive materials within a mechanically matched scaffolding polymer, provides a general framework to guide the future design of artificial smart skins.

Evaluation of transcatheter heart valve biomaterials: Computational modeling using bovine and porcine pericardium.

OBJECTIVE: The durability of bioprosthetic heart valve (BHV) devices, commonly made of bovine (BP) and porcine (PP) pericardium tissue, is partly limited by device calcification and tissue degeneration, which has been associated with pathological levels of mechanical stress. This study investigated the impacts of BP and PP tissues with different thicknesses and tissue mechanical properties in BHV applications. METHODS: Second Harmonic Generation (SHG) imaging was employed to visualize the collagen fibers on each side of the pericardium. Structural constitutive modeling that incorporates collagen fiber distribution obtained from multiphoton microscopy for each tissue type were derived to characterize the corresponding biaxial mechanical testing data collected in a previous study. The models were verified through finite element (FE) simulations of the biaxial test and implemented in valve closing simulations. RESULTS: Smooth side collagen fibers were found to correlate with the mechanical response. BHVs with adult (ABP) and calf (CBP) BP tissues had lower maximum principal stresses than those with PP and fetal (FBP) BP tissues. Collagen fiber orientation along the circumferential axis resulted in lower maximum principal stresses and more uniform and symmetric stress distributions throughout the valve. CONCLUSIONS: The use of PP and FBP tissue resulted in higher peak stresses than ABP and CBP tissues in the given valve design. Additionally, ensuring collagen fiber orientation along the circumferential axis led to lower maximum stresses felt by the valve leaflets, which could also improve BHV durability.

Suture dehiscence and collagen content in the human mitral and tricuspid annuli.

Postoperative suture dehiscence is an important mode of short-term mitral and tricuspid valve (MV, TV) repair failure. We sought to evaluate suture pullout forces and collagen density in human atrioventricular valves for a better understanding of the comparative physiology between the valves and the underlying mechanobiological basis for suture retention. Mitral and tricuspid annuli were each excised from hearts from human donors age 60-79 with no history of heart disease (n = 6). Anchor sutures were vertically pulled until tearing through the tissue. Suture pullout force (FP) was measured as the maximum force at dehiscence. Subsequently, tissue samples from each tested suture position were evaluated for collagen content using a standard hydroxyproline assay. Among all mitral positions, no significant differences were detected among positions or regions with mean FP values falling between 6.9 ± 2.6 N (posterior region) and 10.3 ± 4.7 N (anterior region). Among all tricuspid positions, the maximum FP and minimum FP were 24.0 ± 9.2 N (trigonal region) and 4.5 ± 2.6 N (anterior region). Although for the MV, a given sample's collagen content had no correlation to its corresponding FP, the same relationship was significant for the TV. Further, the TV exhibited comparable FP to the MV overall, despite a nearly 40% reduction in collagen content. These findings suggest that sutures placed in the trigonal region of the TV have higher pullout force than those placed along other segments of the annuli. Furthermore, there are likely differences in collagen orientation between the mitral and tricuspid annuli, such that collagen content strongly impacts FP in one, but not the other.

Mechanical and structural analysis of the pulmonary valve in congenital heart defects: A presentation of two case studies.

OBJECTIVE: Congenital Heart Disease (CHD) is the leading cause of pediatric mortality, with many cases affecting the right ventricular outflow tract (RVOT) or pulmonary valve (PV). Understanding the mechanics of the disease condition can provide insight into development of durable repair techniques and bioengineered replacement devices. This work presents a mechanical and structural analysis of the pulmonary valve of two pediatric cases. METHODS: Two PV tissues were excised as part of the operative procedure. One PV was obtained from a 9-month-old with Noonan syndrome (Patient 1) and the other from a 6-month-old with tricuspid atresia (Patient 2). The leaflets were subjected to planar biaxial tensile testing and second harmonic generation (SHG) imaging for mechanical and structural evaluation. RESULTS AND DISCUSSION: Patient 1 exhibited a more anisotropic mechanical response than Patient 2, with sample stiffness on par with that of adult PV tissue. Additionally, both samples showed radial and circumferential alignment of collagen fibers on the ventricularis and fibrosa sides of the leaflets, respectively. Collagen fibers on the fibrosa side were also more crimped than on the ventricularis side.

Comparative mechanical, morphological, and microstructural characterization of porcine mitral and tricuspid leaflets and chordae tendineae.

BACKGROUND: Healthy function of tricuspid valve (TV) structures is essential to avoid tricuspid regurgitation (TR) and may significantly improve disease prognosis. Mitral valve (MV) structures have been extensively studied, but little is known about the TV and right-sided heart diseases. Therefore, clinical decisions and finite element (FE) simulations often rely heavily on MV data for TV applications, despite fundamentally different mechanical and physiological environments. METHOD/RESULTS: To bridge this gap, we performed a rigorous mechanical, morphological, and microstructural characterization of the MV and TV leaflets and chordae in a porcine model. Planar biaxial testing, uniaxial testing, second harmonic generation imaging and Verhoeff Van Gieson staining were performed. Morphological parameters, tissue moduli, extensibility, and anisotropy were quantified and compared. No major differences in leaflet mechanics or structure were found between TV and MV; chordal mechanics, morphology, and structure were found to compensate for anatomical and physiological loading differences between the valves. No differences in chordal mechanics were observed by insertion point within a leaflet; the septal tricuspid leaflet (STL) and posterior mitral leaflet (PML) did not have distinguishable strut chords, and the STL had the shortest chords. Within a valve, chords from septally-located leaflets were more extensible. MV chords were stiffer. CONCLUSIONS: This study presents the first rigorous comparative mechanical and structural dataset of MV and TV structures. Valve type and anatomical location may be stronger predictors of chordal mechanics. Chords from septally-located leaflets differ from each other and from their intravalvular counterparts; they merit special consideration in surgical and computational applications. STATEMENT OF SIGNIFICANCE: A better understanding of the tricuspid valve (TV) and its associated structures is important for making advancements towards the repair of tricuspid regurgitation. Mitral valve structures have been extensively studied, but little is known about the TV and right-sided heart diseases. Clinical decisions and computational simulations often rely heavily on MV data for TV applications, despite fundamentally different environments. We therefore performed a rigorous mechanical, morphological, and microstructural characterization of atrioventricular leaflets and chordae tendineae in a porcine model. Finding that valve type and anatomical location may be strong predictors of chordal mechanics, chords from septally-located leaflets differ from each other and from their intravalvular counterparts; they merit special consideration in surgical and computational applications.

Pathological Remodeling of Mitral Valve Leaflets from Unphysiologic Leaflet Mechanics after Undersized Mitral Annuloplasty to Repair Ischemic Mitral Regurgitation.

Background Undersized ring annuloplasty is a commonly used surgical repair for ischemic mitral regurgitation, in which annular downsizing corrects regurgitation, but alters valve geometry and elevates tissue stresses. In this study, we investigated if unphysiological leaflet kinematics after annuloplasty might cause pathogenic biological remodeling of the mitral valve leaflets, and if preserving physiologic leaflet kinematics with a better technique can moderate such adverse remodeling. Methods and Results Twenty-nine swine were induced with ischemic mitral regurgitation, and survivors were assigned to groups: 7 underwent annuloplasty, 12 underwent annuloplasty with papillary-muscle approximation, 6 underwent papillary-muscle approximation, and 3 were sham controls. Pre-and post-surgery leaflet kinematics were measured, and valve tissue was explanted after 3 months to assess biological changes. Anterior leaflet excursion was unchanged across groups, but persistent tethering was observed with annuloplasty. Posterior leaflet was vertically immobile after annuloplasty, better mobile with the combined approach, and substantially ( P=0.0028) mobile after papillary-muscle approximation. Procollagen-1 was higher in leaflets from annuloplasty compared with the other groups. Heat shock protein-47 and lysyl oxidase were higher in groups receiving annuloplasty compared with sham. α- SMA was elevated in leaflets from animals receiving an annuloplasty, indicating activation of quiescent valve interstitial cells, paralleled by elevated transforming growth factor-ß expression. Conclusions This is the first study to demonstrate that surgical valve repairs that impose unphysiological leaflet mechanics have a deleterious, pathological impact on valve biology. Surgeons may need to consider restoring physiologic leaflet stresses as well as valve competence, while also exploring pharmacological methods to inhibit the abnormal signaling cascades.

Biomechanical properties of the thoracic aorta in Marfan patients.

BACKGROUND: Marfan syndrome (MFS), a genetic disorder of the connective tissue, has been strongly linked to dilation of the thoracic aorta, among other cardiovascular complications. As a result, MFS patients frequently suffer from aortic dissection and rupture, contributing to the high rate of mortality and morbidity among MFS patients. Despite the significant effort devoted to the investigation of mechanical and structural properties of aneurysmal tissue, studies on Marfan aneurysmal biomechanics are scarce. Ex vivo mechanical characterization of MFS aneurysmal tissue can provide a better insight into tissue strength outside the physiologic loading range and serve as a basis for improved risk assessment and failure prediction. METHODS: The mechanical and microstructural properties of MFS aneurysmal thoracic aorta (MFS, n=15, 39.5±3.91 years), non-MFS aneurysmal thoracic aorta (TAA, n=8, 52.8±4.9 years), healthy human thoracic aorta (HH, n=8, 75.4±6.1 years), and porcine thoracic aorta (n=10) are investigated. Planar biaxial tensile testing and uniaxial failure testing were utilized to characterize the mechanical and failure properties of the tissue, respectively. Verhoeff-Van Gieson (VVG) and PicroSirius Red stains were utilized to visualize the elastin and collagen fiber architecture, respectively. RESULTS: MFS tissue was found to have age-dependent but diameter-independent mechanical, structural, and morphological properties, also showing extensive elastin fiber degradation. Non-MFS thoracic aneurysmal aorta was thicker and stiffer than age-matched MFS tissue. Moreover, non-MFS thoracic aneurysmal mechanics resembled closely the mechanics of older healthy human tissue. Younger MFS tissue (<40 years) exhibited similar mechanical and structural properties to aged porcine tissue. CONCLUSIONS: Both age and aneurysmal presence were found to be factors associated with increased stiffness in aortic tissue, and aortic diameter was not a significant determinant of mechanical property deterioration. Additionally, the presence of MFS was found to induce stiffening of the thoracic aorta, although not to the extent of the non-MFS aneurysm.

Evaluation of transcatheter heart valve biomaterials: Biomechanical characterization of bovine and porcine pericardium.

OBJECTIVE: Bovine pericardium (BP) has been identified as a choice biomaterial for the development of surgical bioprosthetic heart valves (BHV) and transcatheter aortic valves (TAV). Porcine pericardium (PP) and younger BP have been suggested as candidates TAV leaflet biomaterials for smaller-profile devices due to their reduced thickness; however, their mechanical and structural properties remain to be fully characterized. This study characterized the material properties of chemically treated thick (PPK) and thin (PPN) PP, as well as fetal (FBP), calf (CBP) and adult (ABP) BP tissues in order to better understand their mechanical behavior. METHODS: Planar biaxial testing and uniaxial failure testing methods were employed to quantify tissue mechanical responses and failure properties. Fiber characteristics were examined using histological analysis. RESULTS: ABP and CBP tissues were significantly stiffer and stronger than the younger FBP tissues. Histological analysis revealed a significantly larger concentration of thin immature collagen fibers in the FBP tissues than in the ABP and CBP tissues. While PP tissues were thinnest, they were stiffer and less extensible than the BP tissues. CONCLUSIONS: Due to comparable mechanical properties but significantly reduced thickness, CBP tissue may be a more suitable material for TAV manufacturing than ABP tissue. FBP tissue, despite its reduced thickness and higher flexibility, was weaker and should be studied in more detail. Although PP tissues are the thinnest, they were least extensible and failed at earlier strain than BP tissues. The differences between PP and BP tissues should be further investigated and suggest that they should not be used interchangeably in the manufacturing of TAV.

Quantification and comparison of the mechanical properties of four human cardiac valves.

OBJECTIVE: Although having the same ability to permit unidirectional flow within the heart, the four main valves-the mitral valve (MV), aortic (AV), tricuspid (TV) and pulmonary (PV) valves-experience different loading conditions; thus, they exhibit different structural integrity from one another. Most research on heart valve mechanics have been conducted mainly on MV and AV or an individual valve, but none quantify and compare the mechanical and structural properties among the four valves from the same aged patient population whose death was unrelated to cardiovascular disease. METHODS: A total of 114 valve leaflet samples were excised from 12 human cadavers whose death was unrelated to cardiovascular disease (70.1±3.7years old). Tissue mechanical and structural properties were characterized by planar biaxial mechanical testing and histological methods. The experimental data were then fitted with a Fung-type constitutive model. RESULTS: The four valves differed substantially in thickness, degree of anisotropy, and stiffness. The leaflets of the left heart (the AV leaflets and the anterior mitral leaflets, AML) were significantly stiffer and less compliant than their counterparts in the right heart. TV leaflets were the most extensible and isotropic, while AML and AV leaflets were the least extensible and the most anisotropic. Age plays a significant role in the reduction of leaflet stiffness and extensibility with nearly straightened collagen fibers observed in the leaflet samples from elderly groups (65years and older). CONCLUSIONS: Results from 114 human leaflet samples not only provided a baseline quantification of the mechanical properties of aged human cardiac valves, but also offered a better understanding of the age-dependent differences among the four valves. It is hoped that the experimental data collected and the associated constitutive models in this study can facilitate future studies of valve diseases, treatments and the development of interventional devices. STATEMENT OF SIGNIFICANCE: Most research on heart valve mechanics have been conducted mainly on mitral and aortic valves or an individual valve, but none quantify and compare the mechanical and structural properties among the four valves from the same relatively healthy elderly patient population. In this study, the mechanical and microstructural properties of 114 leaflets of aortic, mitral, pulmonary and tricuspid valves from 12 human cadaver hearts were mechanically tested, analyzed and compared. Our results not only provided a baseline quantification of the mechanical properties of aged human valves, but a age range between patients (51-87years) also offers a better understanding of the age-dependent differences among the four valves. It is hoped that the obtained experimental data and associated constitutive parameters can facilitate studies of valve diseases, treatments and the development of interventional devices.