## 2 Background and History of MIPs  
Molecularly imprinting technique (MIT) was first reported in 1972 by [PERSON] and [PERSON] [8], and has subsequently been adopted by many research groups. The preparation of MIPs has the benefit of being simple, fast, economical, and robust, however, some challenges remain. One of the most important aspects to be considered, if opting for MIT, is the proper selection of the template, solvent and functional monomer, all guided by the nature of application [9]. Monomer selection depends on the physical-chemical properties of the template, so that its functional groups can interact with the monomer to form stable supramolecular complexes, involving non-covalent, coordinative, or covalent bonding. The stability of the prepolymerization complex is promoted by either acid-base functional complementarity, hydrogen bond donor-acceptor, or other types of weak interactions between the participating molecules, i.e., template and functional monomers. Usually, a 1:4 template:monomer ratio provides an acceptable stability for the complex [10]. Figure 2 illustrates the simplified MIP synthesis. Polymerization also requires cross-linkers to ensure the structural stability of the polymeric scaffold and to increase its porosity. The type of cross-linker is related to the preservation of the binding cavity's shape, as it directly influences the physico-chemical  
Figure 2: Schematic representation of MIP synthesis. The illustration presents the simplified process of molecular imprinting, wherein a mixture of template, functional monomer and cross-linker generates a highly cross-linked polymer, under certain initiating reaction conditions. and mechanical properties of the polymers. The most common cross-linker is ethylene glycol dimethacrylate (EGDMA), due to the increased mechanical stability provided. Other possible cross-linkers are divinylbenzene (DVB) or trimethylolpropane trimethacrylate (TRIM). Generally, the resulting MIPs are characterized by high structural robustness in a wide range of pH, solvents and temperature [10]. Furthermore, the nature and concentration of a cross-linker is closely connected to other characteristics. A low concentration of cross-linker leads to poor stability and the faster release of the template, while hydrophilic agents increase biocompatibility [5]. The imprinting process is generally similar when designing MIPs for either analytical applications or drug delivery. However, each application requires a specific synthetic approach. MIPs were initially developed for analytical purposes; therefore, most of the later designed polymers intended for drug delivery were made using the same acrylic monomers, via non-covalent imprinting. The main adjustment when changing the field from analytical purposes to drug delivery is a decrease in the cross-linker ratio. For analytical applications, such as molecular recognition, sensing, or separations, MIPs should be highly cross-linked to ensure a highly specific rebinding of the template molecule through their rigid cavities. For drug delivery, however, a lower degree of cross-linking is desirable in order to provide tunable release kinetics. While the imprinting factor is crucial for MIPs employed in analysis, their drug loading capacity becomes more relevant in the field of drug delivery. These features are interconnected, as a higher binding affinity might imply a higher drug loading capacity and extended drug release. Selected monomers, cross-linkers, and porogens for drug delivery should be biocompatible and biodegradable in order to reduce the possible negative impact on the viability of healthy cells [4; 11]. The solvent also plays a crucial role in the process, as it directly influences the strength of the template monomer interaction. Solvents that have low dielectric constants are usually preferred (chloroform or toluene), as they tend to stabilize the electrostatic interactions and hydrogen bonds.