# Biomedical Application of Cyclodextrin Polymers Cross-Linked via Dianhydrides of carboxylic Acids
## 3 Generation of CD-NS  
CD-NS can be divided into four generations in regards to their properties [14; 25; 26].  
First-generation. NS are obtained by a simple reaction of cyclodextrin with a cross-linking agent. They can be grouped into four types depending on the functional group of a given cross-linking agent [14]:* Urethane (or carbamate) CD-NS--are obtained from CDs cross-linked via diisocyanates and are characterized by a rigid structure, high degree of resistance to chemical degradation, and small range of swelling in aqueous and organic environments. For example, a cross-linking agent is hexamethylene diisocyanate or 2,4-diisocyanate toluene [17];
* Carbonate CD-NS--are formed from CDs cross-linked via active carbonyl compounds; for example, 1,1'-carbonyldiimidazole, triphosphate, and diphenyl carbonate. These nanosponges are characterized by short cross-linking bridges, limited swelling capacity, and good stability in the acidic and weak in the alkaline environment [27];
* Ester CD-NS--are synthesized from CDs and dianhydrides or di/polycarboxylic acids. The examples regarding, pyromellitic dianhydride (PMDA), ethylenediamine-tetraacetic dianhydride (EDTA), butane tetracarboxylic acid dianhydride, and citric acid are used. Unlike the previous two types, the ester CD-NS can absorb significant amounts of water and form hydrogels. The degree of cross-linking affects the swelling capacity due to water absorption. A smaller degree of cross-linking can lead to the absorption of more water. In addition, less chemically stable as it can be more easily hydrolyzed in an aqueous environment than urethanes or carbonates [28];
* Ether CD-NS--are the products of the reaction between cyclodextrins and cross-linking agents with epoxide groups. Examples of such compounds regard epichlorohydrin, bisphenol A diglycidylI ether, ethylene glycol, and diglycidylI ether. Even though epichlorohydrin is toxic, most research still focuses on it. In this case, CD-NS exhibit high chemical resistance and controlled swelling capacity [29, 30]. Their synthesis is carried out in an alkaline environment [31].  
Second generation. Polymers with new properties and applications can be obtained by introducing different moieties into the CD-NS structure. Functional groups can be introduced in the following three ways: functionalization after cross-linking, functionalization before cross-linking, and functionalization simultaneously with cross-linking. In the first case, mainly the polymer surface is modified whereas, in other situations, the entire NS molecule is functionalized. However, the introduction of side groups into cyclodextrin molecules, prior to polymerization, can decrease the degree of cross-linking or even prevent it [14, 32].  
Third generation. Stimuli-sensitive nanosponges respond to external changes by changing their properties; e.g., shape, color, and permeability. This ability is derived from the behavior of the stimulus at the molecular, supramolecular level, or even by its morphology. NS can be stimulated by the temperature, electromagnetic field, redox potential, and pH. By controlling the relevant parameters associated with stimuli, it can lead to the controlled transport of substances or release of electric charge. For example, CD-NS can behave as hidden carriers and release the drug under appropriate physiological conditions, thus extending the lifetime of the drug [14, 33].  
Fourth generation. Molecularly imprinted polymers (MIP) are based on CD resulted from the non-covalent interactions between the guest molecule (template) and the monomer in the presence of a cross-linking agent during polymerization. The template gives nanosponges the ability to recognize molecules. Later, the template is removed, and the remaining voids adjust to the shape and size of the target molecule. The obtained MIP has specific molecular recognition, high selectivity, and affinity to the target molecule [14, 20, 34].