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AbstractSickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized “endothelialized” microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD. 

Red blood cell (RBC) disorders such as sickle cell disease affect billions worldwide. While much attention focuses on altered properties of aberrant RBCs and corresponding hemodynamic changes, RBC disorders are also associated with vascular dysfunction, whose origin remains unclear and which provoke severe consequences including stroke. Little research has explored whether biophysical alterations of RBCs affect vascular function. We use a detailed computational model of blood that enables characterization of cell distributions and vascular stresses in blood disorders and compare simulation results with experimental observations. Aberrant RBCs, with their smaller size and higher stiffness, concentrate near vessel walls (marginate) because of contrasts in physical properties relative to normal cells. In a curved channel exemplifying the geometric complexity of the microcirculation, these cells distribute heterogeneously, indicating the importance of geometry. Marginated cells generate large transient stress fluctuations on vessel walls, indicating a mechanism for the observed vascular inflammation. 

BME HealthReach is an educational outreach program where undergraduate BME students participate in an out-of-class design thinking course to create and teach interactive STEM activities to K-12 students, where children with chronic illnesses are the primary clients. We detail research that seeks to answer the following: (1) what impact does this out-of-class design course have? (2) how does this course contribute to the entrepreneurial mindset, including promoting connection-making and creating social value/ relationships? and (3) do the STEM activities achieve the educational learning objectives? 

Abstract Ultraviolet (UV) spectroscopy is a powerful tool for quantitative (bio)chemical analysis, but its application to molecular imaging and microscopy has been limited. Here we introduce ultraviolet hyperspectral interferometric (UHI) microscopy, which leverages coherent detection of optical fields to overcome significant challenges associated with UV spectroscopy when applied to molecular imaging. We demonstrate that this method enables quantitative spectral analysis of important endogenous biomolecules with subcellular spatial resolution and sensitivity to nanometer-scaled structures for label-free molecular imaging of live cells.