  Hyaluronic acid is an abundant polyelectrolyte in the human body that forms
extracellular hydrogels in connective tissues. It is essential for regulating
tissue biomechanics and cell-cell communication, yet hyaluronan overexpression
is associated with pathological situations such as cancer and multiple
sclerosis. Due to its enormous molecular weight (in the range of millions of
Daltons), accumulation of hyaluronan hinders transport of macromolecules
including nutrients and growth factors through tissues and also hampers drug
delivery. However, the exact contribution of hyaluronan to tissue penetrability
is poorly understood due to the complex structure and molecular composition of
tissues. Here we reconstitute biomimetic hyaluronan gels and systematically
investigate the effects of gel composition and crosslinking on the diffusion of
microscopic tracer particles. We combine ensemble-averaged measurements via
differential dynamic microscopy with single-particle tracking. We show that the
particle diffusivity depends on the particle size relative to the network pore
size and also on the stress relaxation dynamics of the network. We furthermore
show that addition of collagen, the other major biopolymer in tissues, causes
the emergence of caged particle dynamics, which is not present in the
one-component systems. Our findings are useful for understanding macromolecular
transport in tissues and for designing biomimetic extracellular matrix
hydrogels for drug delivery and tissue regeneration.
