The dynamics of blood flow in the smallest vessels and passages of the human body, where the cellular character of blood becomes prominent, plays a dominant role in the transport and exchange of solutes. Recent studies have revealed that the microhaemodynamics of a vascular network is underpinned by its interconnected structure, and certain structural alterations such as capillary dilation and blockage can substantially change blood flow patterns. However, for extravascular media with disordered microstructure (e.g. the porous intervillous space in the placenta), it remains unclear how the medium's structure affects the haemodynamics. Here, we simulate cellular blood flow in simple models of canonical porous media representative of extravascular biological tissue, with corroborative microfluidic experiments performed for validation purposes. For the media considered here, we observe three main effects: first, the relative apparent viscosity of blood increases with the structural disorder of the medium; second, the presence of red blood cells (RBCs) dynamically alters the flow distribution in the medium; third, symmetry breaking introduced by moderate structural disorder can promote more homogeneous distribution of RBCs. Our findings contribute to a better understanding of the cell-scale haemodynamics that mediates the relationship linking the function of certain biological tissues to their microstructure. 

Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media

Cellular aggregation dictates universal spreading behaviour of a whole-blood drop on a paper strip.

Microcapsules with liquid cores encapsulated by thin membranes have many applications in science, medicine and industry. In this paper, we design a suspension of microcapsules which can flow and deform like red blood cells (RBCs), as a valuable tool to investigate microhaemodynamics. A reconfigurable and easy-to-assemble 3D nested glass capillary device is used to robustly fabricate water-oil-water double emulsions which are then converted into spherical microcapsules with hyperelastic membranes by cross-linking the polydimethylsiloxane (PDMS) layer coating the droplets. The resulting capsules are monodisperse to within 1% and can be made in a wide range of size and membrane thickness. We use osmosis to deflate by 36% initially spherical capsules of diameter 350 μm and a membrane thickness of 4% of their radius. Hence, we can match the reduced volume of RBCs but not their biconcave shape, since our capsules adopt a buckled shape. We compare the propagation of initially spherical and deflated capsules under constant volumetric flow in cylindrical capillaries of different confinements. We find that only deflated capsules deform broadly like RBCs over a similar range of capillary numbers Ca - the ratio of viscous to elastic forces. Similarly to the RBCs, the microcapsules transition from a symmetric 'parachute' to an asymmetric 'slipper'-like shape as Ca increases within the physiological range, demonstrating intriguing confinement-dependent dynamics. In addition to biomimetic RBC properties, high-throughput fabrication of tunable ultra-soft microcapsules could be further functionalized and find applications in other areas of science and engineering.

/pdf/robust-fabrication-of-ultra-soft-tunable-pdms-microcapsules-16qac0vf.pdf

Robust fabrication of ultra-soft tunable PDMS microcapsules as a biomimetic model for red blood cells.

In this review, we provide a summary of the state-of-the-art in the in silico modelling of cerebral blood flow (CBF) and its application in in silico clinical trials. CBF plays a key role in the transport of nutrients, including oxygen and glucose, to brain cells, and the cerebral vasculature is a highly complex, multi-scale, dynamic system that acts to ensure that supply and demand of these nutrients are continuously balanced. It also plays a key role in the transport of other substances, such as recombinant tissue-plasminogen activator, to brain tissue. Any dysfunction in CBF can rapidly lead to cell death and permanent damage to brain regions, leading to loss of bodily functions and death. The complexity of the cerebral vasculature and the difficulty in obtaining accurate anatomical information combine to make mathematical models of CBF key in understanding brain supply, diagnosis of cerebrovascular disease, quantification of the effects of thrombi, selection of the optimum intervention, and neurosurgical planning. Similar in silico models have now been widely applied in a variety of body organs (most notably in the heart), but models of CBF are still far behind. The increased availability of experimental data in the last 15 years however has enabled these models to develop more rapidly and this progress is the focus of this review. We thus present a brief review of the cerebral vasculature and the mathematical foundations that underpin CBF in both the microvasculature and the macrovasculature. We also demonstrate how such models can be applied in the context of cerebral diseases and show how this work has recently been expanded to in silico trials for the first time. Most work to date in this context has been performed for ischaemic stroke or cerebral aneurysms, but these in-silico models have many other applications in neurodegenerative diseases where mathematical models have a vital role to play in testing hypotheses and providing test beds for clinical interventions.

Review of in silico models of cerebral blood flow in health and pathology

The natural habitat of most cells consists of complex and disordered 3D microenvironments with spatiotemporally dynamic material properties. However, prevalent methods of in vitro culture study cells under poorly biomimetic 2D confinement or homogeneous conditions that often neglect critical topographical cues and mechanical stimuli. It has also become increasingly apparent that cells in a 3D conformation exhibit dramatically altered morphological and phenotypical states. In response, efforts toward designing biomaterial platforms for 3D cell culture have taken centerstage over the past few decades. Herein, we present a broad overview of biomaterials for 3D cell culture and 3D bioprinting, spanning both monolithic and granular systems. We first critically evaluate conventional monolithic hydrogel networks, with an emphasis on specific experimental requirements. Building on this, we document the recent emergence of microgel-based 3D growth media as a promising biomaterial platform enabling interrogation of cells within porous and granular scaffolds. We also explore how jammed microgel systems have been leveraged to spatially design and manipulate cellular structures using 3D bioprinting. The advent of these techniques heralds an unprecedented ability to experimentally model complex physiological niches, with important implications for tissue bioengineering and biomedical applications.

Design approaches for 3D cell culture and 3D bioprinting platforms.

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Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media