A microfluidic platform to study the effects of vascular architecture and oxygen gradients on sickle blood flow

Abstract

Objective Our goal was to develop a model of the microvasculature that would allow us to quantify changes in the rheology of sickle blood as it traverses the varying vessel sizes and oxygen tensions in the microcirculation. Methods We designed and implemented a microfluidic model of the microcirculation that comprises a branching microvascular network and physiologic oxygen gradients. We used computational modeling to determine the parameters necessary to generate stable, linear gradients in our devices. Sickle blood from 6 unique patients was perfused through the microvascular network and subjected to varying oxygen gradients while we observed and quantified blood flow. Results We found that all sickle blood samples fully occluded the microvascular network when deoxygenated, and we observed that sickle blood could cause vaso-occlusions under physiologic oxygen gradients during the microvascular transit time. The number of occlusions observed under 5 unique oxygen gradients varied among the patient samples, but we generally observed that the number of occlusions decreased with increasing inlet oxygen tension. Conclusions The model system we have developed is a valuable tool to address fundamental questions about where in the circulation sickle cell vaso-occlusions are most likely to occur and to test new therapies.

5‐(Hydroxymethyl)furfural restores low‐oxygen rheology of sickle trait blood in vitro

“…This study demonstrates a novel application of this microfluidic experimental platform in the assessment of rheological responses to pharmacological interventions for SCT. This experimental system has previously been used to investigate SCD pathophysiology, including rheological mechanisms of vaso‐occlusion (Higgins et al , ; Higgins et al , ; Lu et al , ; Lu et al , ), correlations of in vitro and in vivo phenotypes (Wood et al , ), and the use of in vitro SCT phenotypes as a treatment target for SCD (Lu et al , ). There are currently no good in vitro biomarkers for the management of SCD (Kalpatthi & Novelli, ), and the need for their development has increased dramatically recently with the advent of experimental therapies for SCD whose optimization and comparative assessment crucially depends on the availability of validated in vitro markers (Benz et al , ).…”

“…Because 5HMF may meet the stringent safety requirements for any viable approach for managing risks associated with SCT, and because it has a potentially effective mechanism of action, we studied its effect on the low‐oxygen rheology of SCT blood in vitro using a microfluidic platform (Fig ) that we previously showed can recapitulate the low‐oxygen rheological behaviour of blood from individuals with SCT and SCD (Higgins et al , ; Wood et al , ; Lu et al , ; Lu et al , ; Lu et al , ). It is important to emphasize that this study does not alter the currently evolving assessment of the clinical significance of the risks associated with SCT.…”

“…SCT leads to a sickle haemoglobin (HbS) fraction in red blood cells (RBCs) of roughly 40%, lower than the ~80% or more typical for sickle cell disease (SCD) (Noguchi et al , ; Bain, ; Lu et al , ). This lower HbS fraction, and thus lower HbS concentration, in SCT RBCs reduces haemoglobin polymerization and cell sickling until the oxygen tension drops much lower than is necessary for significant polymer to form in SCD RBCs (Noguchi et al , ; Bunn, ; Higgins et al , ; Barabino et al , ; Wood et al , ; Lu et al , ; Eaton & Bunn, ; Lu et al , ; Lu et al , ). SCT provides protection against severe outcomes in malaria infection, with one study finding that malaria patients with SCT had about a fourfold lower risk of requiring hospitalization than those with two normal (AA) HBB alleles (Uyoga et al , ).…”

Endothelial cell culture in microfluidic devices for investigating microvascular processes

“…24 Lu et al report a system in which they introduce vessel size and oxygen gradients into their in vitro system in order to simulate the various degrees of blood oxygenation throughout the in vivo vasculature. 25 Lamberti et al reported a system in which a microfluidic channel is fabricated in close proximity to a large "tissue" compartment (i.e., a compartment in the microfluidic device that can be filled with different cell types to recapitulate multiple tissue environments) separated by a porous barrier. 26 This system enables the study of transport between the vasculature and the desired tissue of study.…”

Microfluidics Technologies and Approaches for Studying the Microcirculation

“…4 The next group of articles emphasizes the use of microfluidics for evaluating blood cell deformability and aggregation during network perfusion with a focus on gaining insights into the effects of sickle cell disease on altered red blood cell stiffness and function. [5][6][7][8][9] Collectively, the articles in this issue exemplify the value of applying microfluidic fabrication techniques for microvascular research and, more broadly, the potential for incorporating emergent technologies to learn more about the complex and dynamic physiology of the microcirculation.…”