## 2 Background and History of MIPs
Solvents with higher dielectric constants (acetonitrile) may also be used, although the resulting MIPs will have a lower affinity to rebind the template [10]. Whilst they pose great concerns regarding environmental toxicity, the conventional solvents used for MIP synthesis are acetonitrile, methanol, chloroform, tetrahydrofuran, toluene, dichlorethane and \(N\),\(N\)-dimethylformamide [12]. The solvent's nature is a general quality criterion frequently omitted from studies, which becomes highly relevant when studying MIPs in vivo. Most MIPs intended for drug delivery applications are fabricated with the use of aprotic and low polarity organic solvents for the preservation of hydrogen bonds. Due to the possibility of additional or unexpected toxicity issues, residual organic solvents are unsuitable for drug delivery applications. In addition to their potential for inducing cellular damage, porogenic solvents also influence the polymer's morphology, and could negatively affect their release kinetics. Hence, an aqueous media would be ideal, and is sometimes required, for conducting MIP synthesis [11]. Moving from solution-based synthesis to solid-phase synthesis (SPS) represented another important milestone in the development of MIP-based DDS. In SPS, the template molecule is immobilized on a solid phase and polymerization occurs around it, generating standardized imprinted nanoparticles. The main benefit of using SPS is the low polydispersity index of the resulting formulation and a more homogenous distribution of the binding sites, which occurs as a consequence of the template's orientation on the solid phase. Moreover, the covalent surface immobilization of the template enables the removal of the low-binding polymers prior to the elution of the imprinted particles, while offering a more homogenous binding affinity to the latter fraction, as well as the facile reusability of the surface bound template. Therefore, SPS has been successfully adopted for the fabrication of nanoMIPs with reproducible features and enhanced release kinetics [5]. Although an empirical approach has, until recently, been used for the fabrication of MIPs, new methods for a more rational design have emerged. These include computational simulation-aided methods and rational algorithms. Computational methodscombine quantum and statistical mechanics to simulate static or dynamic molecular interactions. Their advantages include cost-effectiveness, prediction of template-monomer conformational interactions, simulation of the appropriate composition and molar ratio of the pre-polymerization mixture. The methods used for theoretical simulations in MIP design include molecular mechanics (MM) [13], molecular dynamics (MD) [14], and quantum mechanics (QM) [15]. QM provides the highest accuracy for choosing the initial direction of interacting molecules, while MM is the most time- and cost-effective in terms of reagent and solvent use. The complexity of calculations expands exponentially with QM; thus, the most widely used method for complex mixtures is MD. Through MD, one can optimize the molar ratio between the template, monomer, and cross-linker. Through computational methods, the binding energy between the template and functional monomer is simulated and calculated. High binding energy means high selectivity and binding characteristics of designed MIPs. Moreover, these methods make it possible to identify and study the mechanisms underlying MIP formation on a molecular basis. Molecular modelling has been widely applied for the optimization of various materials as it can lower production costs, analysis and synthesis time, as well as the consumption of organic solvents or other polluting reagents. The rational design of MIPs is also based on the nature of the template. If the template is a macromolecule, simulation with QM is not feasible due to the high computational time and risk for errors. With MM and MD, the operation is faster and more accurate for complex mixtures or imprinted templates [16].