From Microscale to Macroscale: Nine Orders of Magnitude for a Comprehensive Modeling of Hydrogels for Controlled Drug...

Because of their inherent biocompatibility and tailorable network design, hydrogels meet an increasing interest as biomaterials for the fabrication of controlled drug delivery devices. In this regard, mathematical modeling can highlight release mechanisms and governing phenomena, thus gaining a key role as complementary tool for experimental activity. Starting from the seminal contribution given by Flory-Rehner equation back in 1943 for the determination of matrix structural properties, over more than 70 years, hydrogel modeling has not only taken advantage of new theories and the increasing computational power, but also of the methods offered by computational chemistry, which provide details at the fundamental molecular level. Simulation techniques such as molecular dynamics act as a "computational microscope" and allow for obtaining a new and deeper understanding of the specific interactions between the solute and the polymer, opening new exciting possibilities for an in silico network design at the molecular scale. Moreover, system modeling constitutes an essential step within the "safety by design" paradigm that is becoming one of the new regulatory standard requirements also in the field-controlled release devices. This review aims at providing a summary of the most frequently used modeling approaches (molecular dynamics, coarse-grained models, Brownian dynamics, dissipative particle dynamics, Monte Carlo simulations, and mass conservation equations), which are here classified according to the characteristic length scale. The outcomes and the opportunities of each approach are compared and discussed with selected examples from literature.