**1. Introduction**

Drug delivery systems grounded on hydrogels (HGs) are interesting because of their high biocompatibility and biodegradability. These properties are especially relevant for materials used for biomedical engineering applications, an example of which may be drug delivery or tissue engineering [1–3]. HGs are water-swollen polymeric networks containing chemical or physical cross-links able to absorb large quantities of water or biological fluids [4]. HGs have a variety of structures, architectures, sizes (from centimetres to sub-nanometres), and functions, and together with other properties, these variables determine HG use for drug delivery [1–3,5].

HGs can be prepared from one polymer (homo-polymeric HG), two or more polymers (multi-polymeric HG); they may also contain other nanostructures/nanoparticles in a polymeric network [6–9]. These polymeric networks can be chemically and physically modified imparting new and unusual properties [9–11]. Chemical structures, compositions, biodegradability, biological functions and di fferent physicochemical properties (e.g., mechanical, rheological, spectral, thermosensitive, pH stability) can be modified [2,6,9,12]. These variations influence the performances of HGs and a ffect loading and releasing properties for drugs [7,9,11–15].

HGs can be used to form microparticles, nanoparticles, micelles and films [15,16]. For HG particles, the particle size (macro, micro and nano) determines the route by which HGs can be delivered into the human body [17–21]. For micro- or nano-sized HGs, the e ffects of various physical and chemical factors on drug release should be considered [15,21]. Therefore, drug immobilization in a polymer matrix should be considered in the context of controlled release at target sites. Various in vivo and in vitro drug application techniques have been developed with various therapeutic properties [12,22–24], including antifungal [25–27], antibacterial [28–32], antitumor [33–36], anti-inflammatory [37,38], immunomodulatory [39–41], anti-glycemic [42], antioxidant [32,37,43], tissue repair and regeneration [14,16,44].

The objective of this review is to explore the potential use of HG particles in drug delivery systems with respect to their size (macro, micro and nano). This review also attempts to identify the e ffects of HG particle size and physicochemical properties on biological performance and medical applications. Finally, novel drug delivery methods for enhancing treatments are discussed.

#### **2. Types of Hydrogels**

A gel is a liquid treated with gelling substances, including natural polymers (e.g., agar, alginates, and dextran), semi-synthetic polymers (cellulose derivatives) or synthetic polymers (acrylic and methacrylic acid derivatives) [45]. Lipophilic gels (oleogels) are obtained using oil as the dispersing phase. Hydrophilic gels (hydrogels) are obtained using water as the dispersing phase [46–48]. Due to their similarity to living human tissues, HGs with controlled drug release are widely used in pharmaceuticals. By modifying their compositions and physicochemical properties (e.g., to impart hydrophilic or hydrophobic character), HGs can be used as drug carriers for external or internal use [49].

HGs are classified using di fferent criteria [50]. The simplest criterion is origin, i.e., natural or synthetic [50,51]. Natural HGs are biocompatible, biodegradable [1] and support cell activity. However, natural HGs have low mechanical strength and large inter-batch variety. Proteins such as collagen or polysaccharides (e.g., chitosan, dextran, and alginate) are examples of natural HGs [52–55]. Synthetic HG polymers are prepared from polymerizable monomers, including vinyl acetate, acrylamide, ethylene glycol and lactic acid (made from plants, mostly from corn and sugarcane) [56–59]. Synthetic HGs can be precisely controlled and tailored to achieve desired properties. However, synthetic HGs typically lack bioactivity and have low biodegradability. Hybrid HGs consist of chemically, functionally and morphologically di fferent units [60–65]. Biologically active proteins, peptides, nano/microstructures are constituent parts of hybrid HGs and are connected with each other by physical or chemical forces [60–66]. Because of their construction, hybrid HGs derive their bioactivity from natural materials; furthermore, the easy control over physical and chemical properties of hybrid HGs are due to synthetic material properties [66].

#### *2.1. Physical and Chemical Hydrogels*

HGs can be classified into two groups based on the type of interactions involved in the creation of the network structure. The first group includes chemical solids [47,51,67,68], wherein HGs form three-dimensional (3D) networks with polymer chains are connected by permanent covalent bonds via cross-linking reactions [69]. Characteristic features of chemical HGs include their ability to swell resulting from interactions among the polymer network, water and the density of connections between polymer chains. Chemical HGs are not homogeneous due to the hydrophobic aggregation of cross-linking agents and high cross-link-density clusters [60].

The second group includes physical (reversible) HGs [51,67,68]. These HGs have chains connected by weak hydrogen bonds, ionic bonds and dipolar or hydrophobic interactions excluding those that dissolve before use [68]. These forces result in non-homogeneous HGs [60]. Examples of physical HG are solutions of agar, gelatine, and polyvinyl alcohol [70,71].

These two types of HGs encompass a wide variety of macromolecular structures formed from cross-linked and entangled linear homopolymers and linear, block or graft copolymers [72–74]. The HG networks can be stabilized by reactions of monovalent and polyvalent ions, multiple monovalent ions or complexes containing hydrogen bonds. The properties and applications of these HGs are closely related to cross-linking density, which determines swelling behaviour and the combined properties of solid and liquid phases [51,68,75].

#### *2.2. Conventional and Stimuli-Responsive Hydrogels*

HGs are also classified as conventional and stimuli-responsive. Conventional HGs comprise loosely connected hydrophilic, mostly non-ionic polymers with significant degrees of swelling in water without dissolution [76]. Stimuli-responsive HGs respond to various factors, such as small changes in temperature, ionic strength, pH, electric field, mechanical stress, light and selected substances (Figure 1a) [49,51,77–80]. Stimuli-responsive HGs can be tailored to react to various types of stimuli in the body, including ionic strength, pH and temperature, to act as potential drug carriers [49,51,77].

**Figure 1.** (**a**) Types of stimuli causing HG swelling. (**b**) Schematic illustration of a thermo-reactive HG formation loaded with a drug that uses temperature as a stimulus.
