Abstract
Biomarker development is a key clinical research need in sickle cell disease (SCD). Hemorheological parameters are excellent candidates as abnormal red blood cell (RBC) rheology plays a critical role in SCD pathophysiology. Here we describe a microfluidic device capable of evaluating RBC deformability and adhesiveness concurrently, by measuring their effect on perfusion of an artificial microvascular network (AMVN) that combines microchannels small enough to require RBC deformation, and laminin (LN) coating on channel walls to model intravascular adhesion. Each AMVN device consists of three identical capillary networks, which can be coated with LN (adhesive) or left uncoated (non-adhesive) independently. The perfusion rate for sickle RBCs in the LN-coated networks (0.18 ± 0.02 nL/s) was significantly slower than in non-adhesive networks (0.20 ± 0.02 nL/s), and both were significantly slower than the perfusion rate for normal RBCs in the LN-coated networks (0.22 ± 0.01 nL/s). Importantly, there was no overlap between the ranges of perfusion rates obtained for sickle and normal RBC samples in the LN-coated networks. Interestingly, treatment with poloxamer 188 decreased the perfusion rate for sickle RBCs in LN-coated networks in a dose-dependent manner, contrary to previous studies with conventional assays, but in agreement with the latest clinical trial which showed no clinical benefit. Overall, these findings suggest the potential utility of the adhesive AMVN device for evaluating the effect of novel curative and palliative therapies on the hemorheological status of SCD patients during clinical trials and in post-market clinical practice.
Highlights
Normal human red blood cells (RBCs) can squeeze through capillaries as small as 3 μm in diameter, and generally do not adhere to the endothelial cells that line blood vessels (Mohandas and Gallagher, 2008)
We have previously developed a non-adhesive version of the artificial microvascular network (AMVN) (Shevkoplyas et al, 2006; Burns et al, 2012), which we used extensively to evaluate the effect of various parameters on microvascular network perfusion, including RBC deformability (Shevkoplyas et al, 2006; Burns et al, 2012; Sosa et al, 2014; Piety et al, 2021), hematocrit (Piety et al, 2017; Reinhart et al, 2017a), RBC aggregation (Reinhart et al, 2017b), RBC shape (Piety et al, 2016), and osmolality of the suspending medium (Reinhart et al, 2015b)
Incorporating hemorheological biomarkers (RBC deformability and adhesiveness) into the clinical trial protocols alongside traditional clinical endpoints has the potential to provide a much more informative, mechanistic, and less subjective assessment of the effectiveness of novel sickle cell disease (SCD) therapies (Kucukal et al, 2020; Lu et al, 2020). These two RBC properties are typically assessed in vitro using separate devices, which entirely overlooks the complex interplay between the effect of deformability and adhesiveness on microvascular blood flow observed in vivo
Summary
Normal human red blood cells (RBCs) can squeeze through capillaries as small as 3 μm in diameter, and generally do not adhere to the endothelial cells that line blood vessels (Mohandas and Gallagher, 2008). Sickle RBC Deformability and Adhesiveness due to a genetic defect that distorts the shape of the RBC and renders it more rigid. While more deformable sickle RBCs are generally considered clinically favorable, as they are expected to flow more through the microvasculature, they are associated with greater levels of RBC adhesion and aggregation (Connes et al, 2013; Deng et al, 2019). The interplay between RBC deformability and adhesiveness with respect to their combined effect on microvascular blood flow is complex, and can make clinical interpretation of individual laboratory measurements challenging. Given the profoundly synergistic effect of both deformability and adhesion on blood flow, it is essential that we evaluate these two properties concurrently within a single device
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