An Experimental-Computational Approach to Quantify Blood Rheology in Sickle Cell Disease.

In sickle cell disease, aberrant blood flow due to oxygen-dependent changes in red cell biomechanics is a key driver of pathology. Most studies to date have focused on the potential role of altered red cell deformability and blood rheology in precipitating vaso-occlusive crises. Numerous studies, however, have shown that sickle blood flow is affected even at high oxygen tensions, suggesting a potentially systemic role for altered blood flow in driving pathologies, including endothelial dysfunction, ischemia, and stroke. In this study, we applied a combined experimental-computation approach that leveraged an experimental platform that quantifies sickle blood velocity fields under a range of oxygen tensions and shear rates. We computationally fitted a continuum model to our experimental data to generate physics-based parameters that capture patient-specific rheological alterations. Our results suggest that sickle blood flow is altered systemically, from the arterial to the venous circulation. We also demonstrated the application of this approach as a tool to design patient-specific transfusion regimens. Finally, we demonstrated that patient-specific rheological parameters can be combined with patient-derived vascular models to identify patients who are at higher risk for cerebrovascular complications such as aneurysm and stroke. Overall, this study highlights that sickle blood flow is altered systemically, which can drive numerous pathologies, and this study demonstrates the potential utility of an experimentally parameterized continuum model as a predictive tool for patient-specific care.

A novel perfusion bioreactor promotes the expansion of pluripotent stem cells in a 3D-bioprinted tissue chamber.

While the field of tissue engineering has progressed rapidly with the advent of 3D bioprinting and human induced pluripotent stem cells (hiPSCs), impact is limited by a lack of functional, thick tissues. One way around this limitation is to 3D bioprint tissues laden with hiPSCs. In this way, the iPSCs can proliferate to populate the thick tissue mass prior to parenchymal cell specification. Here we design a perfusion bioreactor for an hiPSC-laden, 3D-bioprinted chamber with the goal of proliferating the hiPSCs throughout the structure prior to differentiation to generate a thick tissue model. The bioreactor, fabricated with digital light projection, was optimized to perfuse the interior of the hydrogel chamber without leaks and to provide fluid flow around the exterior as well, maximizing nutrient delivery throughout the chamber wall. After 7 days of culture, we found that intermittent perfusion (15 s every 15 min) at 3 ml min-1provides a 1.9-fold increase in the density of stem cell colonies in the engineered tissue relative to analogous chambers cultured under static conditions. We also observed a more uniform distribution of colonies within the tissue wall of perfused structures relative to static controls, reflecting a homogeneous distribution of nutrients from the culture media. hiPSCs remained pluripotent and proliferative with application of fluid flow, which generated wall shear stresses averaging ∼1.0 dyn cm-2. Overall, these promising outcomes following perfusion of a stem cell-laden hydrogel support the production of multiple tissue types with improved thickness, and therefore increased function and utility.

Experimental and Mouse-Specific Computational Models of the Fbln4SMKO Mouse to Identify Potential Biomarkers for Ascending Thoracic Aortic Aneurysm.

PURPOSE: To use computational methods to explore geometric, mechanical, and fluidic biomarkers that could correlate with mouse lifespan in the Fbln4SMKO mouse. Mouse lifespan was used as a surrogate for risk of a severe cardiovascular event in cases of ascending thoracic aortic aneurysm. METHODS: Image-based, mouse-specific fluid-structure-interaction models were developed for Fbln4SMKO mice (n = 10) at ages two and six months. The results of the simulations were used to quantify potential biofluidic biomarkers, complementing the geometrical biomarkers obtained directly from the images. RESULTS: Comparing the different geometrical and biofluidic biomarkers to the mouse lifespan, it was found that mean oscillatory shear index (OSImin) and minimum time-averaged wall shear stress (TAWSSmin) at six months showed the largest correlation with lifespan (r2 = 0.70, 0.56), with both correlations being positive (i.e., mice with high OSImean and high TAWSSmin tended to live longer). When change between two and six months was considered, the change in TAWSSmin showed a much stronger correlation than OSImean (r2 = 0.75 vs. 0.24), and the correlation was negative (i.e., mice with increasing TAWSSmin over this period tended to live less long). CONCLUSION: The results highlight potential biomarkers of ATAA outcomes that can be obtained through noninvasive imaging and computational simulations, and they illustrate the potential synergy between small-animal and computational models.