## 3 pH-Responsive Molecularly Imprinted Polymers  
Weak polyelectrolytes, such as poly(carboxylic acid) [97], poly(phosphoric acid) [98] and polyamine [99], contain ionizable groups and are able to accept or donate protons at a specific pH. These pH-sensitive polymers exhibit a conformational change upon variation of the pH which translates into swelling/shrinking behavior when present as gels. Such hydrogels are the most common candidates for pH-responsive systems. In addition, dendrimers such as polyethyleneimine (PEI) modified with methacryl groups was can also reversibly be opened and closed in response to pH [100]. Therefore, MIPs based on pH-responsive polyelectrolytes should demonstrate pH-dependent recognition and such systems have therefore been considered as promising materials for controlled drug delivery [59, 60, 101]. In molecular imprinting, functional monomers like acrylic acid (AAc), methacrylic acid (MAA), maleic acid (MA), and \(N\),\(N\)-dimethylaminoethyl methacrylate (DMAEMA) are often used in order to provide interactions between the polymer and template molecules through hydrogen bond or charge complementarity. Hence, MIPs with the recognition relying on hydrogen bonding or electrostatic interactions always exhibit a pH-responsive binding capacity caused by the pH-induced change of the interaction between templates and the imprinting sites. Based on this principle, a spherical MIP has been reported by [PERSON] _et al_. as a pH-sensitive sustained drug release system for sulfasalzine using MAA as the functional monomer and EgDMA as the cross-linker, respectively. In addition to displaying a more sustained release period compared to then on-imprinted polymers, the imprinted polymers also showed a different release rate at different pH values. When the MIPs were placed in a media with the pH change from 1 to 6.8, a sudden release of sulfasalzine was observed. This can be explained by the carboxylic groups situated at imprinted sites being ionized at pH values higher than their average p\(K_{\mathrm{a}}\). In this state, they do not interact with the template (sulfasalazine) through hydrogen bonding. To expand the application of spherical MIPs for biological samples, the author further prepared a _p_-acetaminophenol (AMP) imprinted polymer with a hydrophilic external layer, which led to a drastic reduction of protein absorption, hence referred to as a restricted access material [102]. When tested as controlled release device in gastrointestinal simulating fluids, the new polymers showed a pH-responsive release, which further confirmed the release mechanism based on the ionization of carboxylic acid groups. The same effect has been observed in some drug delivery systems based on MIPs. Other acidic monomers such as maleic acid (MA) have also been used to obtain pH-responsive MIP [47]. Since it is analogous to MMA and was mentioned in the last section, it will not be presented here reduplicatively. In contrast to the previous systems, [PERSON] _et al_. described another pH-sensitive MIP nanospheres/hydrogel composite for controlled releasing of dexamethasone-21 phosphate disodium (DXP) [59]. The MIP nanospheres based on a basic functional monomer, DMAEMA, exhibited a faster DXP release rate in a pH range of 6.0-7.4, which is an inspiration for suppressing inflammation because inflammation induces an acidic microenvironment. The pH-responsive release process mainly resulted from the variable ionic interaction (electrostatic interaction) between DXP and DMAEMA in response to pH value. Incorporating the MIP nanospheres into a preformed poly (2-hydroxyethyl methacrylate (HAMA)-_N_-vinyl-2-pyrrolidinone (NVP)-2-methacryloyloxyethyl phosphorylcholine (MPC)) hydrogels formed a pH-sensitive MIP nanospheres/hydrogel composite, which can be designed as a coating on implantable biosensors for potentially suppressing the inflammation. Recently, the metal coordinate bond strategy was also used to fabricate MIH with pH-responsive property and controlled release capacity in aqueous phase.