Comparison of macromolecule permeation through extracellular matrix and hyaluronic acid to inform in vitro testing of subcutaneous therapies

Subcutaneous injection is a widely used route of drug administration, but biopredictive in vitro tools for predicting in vivo bioavailability are not widely established. One such system, the subcutaneous injection site simulator (SCISSOR), incorporates hyaluronic acid (HA) as a model of the subcutaneous extracellular matrix (ECM), which dictates the diffusion of test compounds. However, the native ECM found is markedly more complex. Here for the first time, we compared the permeation of macromolecules with different physicochemical properties (molecular weight and charge) and model biological molecules across the HA hydrogel (used in SCISSOR) and an animal-derived basement membrane extract (BME), an ECM. We coated tissue culture inserts with these matrices as a simple experimental set up to test the permeation. The results show that the two matrices displayed similarities and some notable differences in their performance as barriers for macromolecules of different properties, suggesting that a simple experimental setup utilising biologically derived ECM may act as an inexpensive and accessible tool to predict the in vivo performance of biotherapeutics for SC administration.