Mentoring for INnovative Design Solutions (MINDS): Key Design Considerations and Collaborative Teamwork across Universities for Clinical Translation.

The main purpose of this paper is to share the Mentoring for INnovative Design Solutions (MINDS) Scholars Program developed by Alpha Eta Mu Beta, the International Biomedical Engineering Honor Society. The program's goals are to (1) introduce biomedical engineering students to an open-ended design experience as part of interuniversity teams with industry and faculty mentors, and (2) develop the ability to create designs considering clinical translatability on teams with different backgrounds and areas of expertise. MINDS uses an experiential learning approach to (1) enrich student curricular experiences through inter-institutional collaboration, (2) build engineering design skills, including three key design considerations for clinical/commercial success: intellectual property protection, regulatory strategy, and market identification; and (3) emphasize the importance of end-user considerations. From 2015 to 2022, MINDS has involved 131 students from 50 universities and 22 faculty and industry mentors. Pre- and post-program surveys show statistically significant improvements in understanding of the design process, regulatory strategy, intellectual property protection, market definition, and key product requirements and features. Students also improved communication and teamwork skills. Many students indicated that MINDS participation made them more likely to choose careers that involve product development and/or entrepreneurship. Students attained a working ability to integrate market needs, regulatory strategy, and intellectual property considerations into the design process. They also further developed soft skills, such as conflict resolution, time management, and effective communication through the challenges of inter-institutional collaboration. Additionally, the program heightened their awareness of how biomedical devices and technologies can benefit society.

Discussion: "Comparison of Statistical Methods for Assessing Spatial Correlations Between Maps of Different Arterial Properties" (Rowland, E. M., Mohamied, Y., Chooi, K. Y., Bailey, E. L., and Weinberg, P. D., 2015, ASME J. Biomech. Eng., 137(10), p. 101003): An Alternative Approach Using Segmentation Based on Local Hemodynamics.

The biological response of living arteries to mechanical forces is an important component of the atherosclerotic process and is responsible, at least in part, for the well-recognized spatial variation in atherosusceptibility in man. Experiments to elucidate this response often generate maps of force and response variables over the arterial surface, from which the force-response relationship is sought. Rowland et al. discussed several statistical approaches to the spatial autocorrelation that confounds the analysis of such maps and applied them to maps of hemodynamic stress and vascular response obtained by averaging these variables in multiple animals. Here, we point out an alternative approach, in which discrete surface regions are defined by the hemodynamic stress levels they experience, and the stress and response in each animal are treated separately. This approach, applied properly, is insensitive to autocorrelation and less sensitive to the effect of confounding hemodynamic variables. The analysis suggests an inverse relation between permeability and shear that differs from that in Rowland et al. Possible sources of this difference are suggested.

Endothelial gene expression in regions of defined shear exposure in the porcine iliac arteries.

The effect of hemodynamic shear stress on endothelial gene expression was investigated in the porcine iliac arteries. A novel statistical approach was applied to computational fluid dynamics simulations of the iliac artery flow field to identify three anatomical regions likely to experience high, medium, and low levels of time average shear stress magnitude. Subsequently, endothelial cell mRNA was collected from these regions in the iliac arteries of six swine and analyzed by DNA microarray. Gene set enrichment analysis demonstrated a strong tendency for genes upregulated or downregulated in one of the extreme shear environments (low or high, relative to medium) to be regulated in the same direction in the other extreme shear environment. This tendency was confirmed for specific genes by real-time quantitative PCR. Specifically, beta-catenin, c-jun, VCAM-1, and MCP-1 were all upregulated in low and high shear stress regions relative to the medium shear stress region. eNOS expression was not significantly different in any of the regions. These results are consistent with the notion that endothelial cells chronically exposed to abnormally low or high shear levels in vivo exhibit similar genetic responses. Alternative explanations of this outcome are proposed, and its implications for the role of shear stress in atherogenesis are examined.

Individual and combined effects of shear stress magnitude and spatial gradient on endothelial cell gene expression.

The apparent tendency of atherosclerotic lesions to form in complex blood flow environments has led to many theories regarding the importance of hemodynamic forces in endothelium-mediated atherosusceptibility. The effects of shear stress magnitude and spatial shear stress gradient on endothelial cell gene expression in vitro were examined in this study. Converging-width flow channels were designed to impose physiological ranges of shear stress gradient and magnitude on porcine aortic endothelial cells, and real-time quantitative PCR was performed to evaluate their expression of five genes of interest. Although vascular cell adhesion molecule-1 expression was insensitive to either variable, each of the remaining genes exhibited a unique dependence on shear stress magnitude and gradient. Endothelial nitric oxide synthase showed a strong positive dependence on magnitude but was insensitive to gradient. The expression of c-jun was weakly correlated with magnitude and gradient, without an interaction effect. Monocyte chemoattractant protein-1 expression varied inversely with gradient and also depended on the interaction of gradient with magnitude. Intercellular adhesion molecule-1 expression also exhibited an interaction effect, and increased with shear magnitude. These results support the notion that vascular endothelial cells are able to sense shear gradient and magnitude independently.

Distinct profiles of endothelial gene expression in hyperpermeable regions of the porcine aortic arch and thoracic aorta.

Among the early events associated with atherosclerotic lesion development are increased macromolecular permeability of the endothelium and expression of genes that affect inflammation and oxidative state. The purpose of this study was to measure the expression of several atherosclerosis-related genes in endothelial cells scraped from arch and thoracic regions of the porcine aorta exhibiting elevated permeability. Aortae were collected from six swine that were exposed to circulating Evans blue dye (EBD), a marker of transendothelial albumin permeability. Endothelial cells were scraped from (1) white regions in the thoracic aorta, (2) light blue streaks and blue regions near ostia in the thoracic aorta, and (3) dark blue regions in the aortic arch. Expression levels of several genes were analyzed by real-time quantitative PCR. There were modest differences between the expression levels of several genes in cells from the light blue regions relative to those from white regions. In the dark blue regions, eNOS was drastically downregulated and MCP-1 was upregulated relative to their expression in both the white and light blue regions. The distinct levels of permeability and differences in gene expression profiles exhibited by cells from these different regions of the aorta may reflect corresponding differences in their hemodynamic environments.

Statistical hemodynamics: a tool for evaluating the effect of fluid dynamic forces on vascular biology in vivo.

BACKGROUND: In vivo experimentation is the most realistic approach for exploring the vascular biological response to the hemodynamic stresses that are present in life. Post-mortem vascular casting has been used to define the in vivo geometry for hemodynamic simulation; however, this procedure damages or destroys the tissue and cells on which biological assays are to be performed. METHOD OF APPROACH: Two statistical approaches, regional (RSH) and linear (LSH) statistical hemodynamics, are proposed and illustrated, in which flow simulations from one series of experiments are used to define a best estimate of the hemodynamic environment in a second series. As an illustration of the technique, RSH is used to compare the gene expression profiles of regions of the proximal external iliac arteries of swine exposed to different levels of time-average shear stress. RESULTS: The results indicate that higher shears promote a more atheroprotective expression phenotype in porcine arterial endothelium. CONCLUSION: Statistical hemodynamics provides a realistic estimate of the hemodynamic stress on vascular tissue that can be correlated against biological response.

Effect of hypercholesterolemia on transendothelial EBD-albumin permeability and lipid accumulation in porcine iliac arteries.

Hypercholesterolemia is associated with increased cardiovascular mortality and is known to promote the advancement of atherosclerotic lesions in experimental animal models. Juvenile swine were fed a normal or high-cholesterol diet, and the transendothelial macromolecular permeability of the external iliac arteries of these animals was assessed by measuring the uptake rate of circulating Evans blue dye (EBD). The extent and patterns of lipid-containing lesions were also determined using en face staining with Oil Red O (ORO). Sites of ORO staining often excluded EBD, possibly via the fragmentation of the internal elastic lamina, to which EBD binds. By spatially averaging the EBD uptake in arterial segments relatively free of ORO-positive lesions, it was found that endothelial permeability to albumin was greater in hypercholesterolemic pigs than in those on a normal diet (p=0.056).

Interaction of wall shear stress magnitude and gradient in the prediction of arterial macromolecular permeability.

Large spatial shear stress gradients have anecdotally been associated with early atherosclerotic lesion susceptibility in vivo and have been proposed as promoters of endothelial cell dysfunction in vitro. Here, experiments are presented in which several measures of the fluid dynamic shear stress, including its gradient, at the walls of in vivo porcine iliac arteries, are correlated against the transendothelial macromolecular permeability of the vessels. The fluid dynamic measurements are based on postmortem vascular casts, and permeability is measured from Evans blue dye (EBD) uptake. Time-averaged wall shear stress (WSS), as well as a new parameter termed maximum gradient stress (MGS) that describes the spatial shear stress gradient due to flow acceleration at a given point, are mapped for each artery and compared on a point-by-point basis to the corresponding EBD patterns. While there was no apparent relation between MGS and EBD uptake, a composite parameter, WSS(-0.11) MGS(0.044), was highly correlated with permeability. Notwithstanding the small exponents, the parameter varied widely within the region of interest. The results suggest that sites exposed to low wall shear stresses are more likely to exhibit elevated permeability, and that this increase is exacerbated in the presence of large spatial shear stress gradients.

Spatial comparison between wall shear stress measures and porcine arterial endothelial permeability.

A better understanding of how hemodynamic factors affect the integrity and function of the vascular endothelium is necessary to appreciate more fully how atherosclerosis is initiated and promoted. A novel technique is presented to assess the relation between fluid dynamic variables and the permeability of the endothelium to macromolecules. Fully anesthetized, domestic swine were intravenously injected with the albumin marker Evans blue dye, which was allowed to circulate for 90 min. After the animals were euthanized, silicone casts were made of the abdominal aorta and its iliac branches. Pulsatile flow calculations were subsequently made in computational regions derived from the casts. The distribution of the calculated time-dependent wall shear stress in the external iliac branches was directly compared on a point-by-point basis with the spatially varying in vivo uptake of Evans blue dye in the same arteries. The results indicate that in vivo endothelial permeability to albumin decreases with increasing time-average shear stress over the normal range. Additionally, endothelial permeability increases slightly with oscillatory shear index.