simple micropatterned surfaces to complex matrices with tunable

parameters to be adapted for the cells of interest. These can be

further improved through the incorporation of extracellular matrix

proteins in forms such as hydrogels or matrix coating [3]. The

composition of the ECM in vivo is variable in different tissues as

well as in disease states [4], and this variability can be recapitulated

with in vitro models [5].

Fluid flow is one factor which is less frequently used in cell and

tissue culture, though can also have a major impact on tissue

structure and function. There are many properties which are modu-

lated by tissue perfusion and therefore lacking in static culture

methods, as shown by Fig. 1. The fluid flow causes shear stress

along the membranes of cells which can then impact their function

through mechanotransduction. The exact levels of shear stress can

often be difficult to elucidate in tissue, though it is typically at

microdyne/cm² levels due to the protective function of endothelial

cells around blood vessels [6]. Further improvements brought

about by perfusion are due to the replenishment of medium around

the cells. This ensures a consistent delivery of nutrients, both con-

stituents of the medium such as proteins and growth factors, as well

as components such as dissolved oxygen which are maintained at

consistent levels with the convective mixing in perfusion systems.

This transport is also effective for removal of metabolic waste

products such as lactic acid, as well as other secreted compounds

such as albumin, which can otherwise build up close to the cell

surface to the detriment of the cells. The disruption of unstirred

layers close to the cell surface is also beneficial for this. The variable

concentrations found in static conditions near to membranes are

disrupted with perfusion, resulting in bulk medium concentrations

being the same for regions closer to the cells. This is also beneficial

Fig. 1 Different functions that fluid flow can perform in cells or tissues. (a) Nutrients and signaling molecules

such as hormones are delivered to the cells through the bloodstream. (b) Secreted products and metabolites

from the cells are removed, preventing a buildup of toxic molecules and maintaining osmotic balance. (c) Flow

disrupts unstirred layers which build up close to the cell surface, increasing turnover of nutrients and waste

products in this region. (d) Shear stress provides a mechanical stimulus to cells which can induce specific

functionality or polarization

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Henry W. Hoyle et al.