**2. Hydrogels for drug delivery: mechanism**

Hydrogels are encompassed of 3-D hydrophilic polymer networks [7]. Since hydrogels have hydrophilic functional groups attached to the 3-D polymeric network they can absorb a huge volume of water [4]. The capability to hold water within the interconnected polymeric network aids them to swell and shrink appropriately and in turn, helps them in the application of drug delivery. Hydrogels possess porosity and compatibility with aqueous conditions hence they are considered highly promising materials for drug release [8]. Moreover, the tunable properties of hydrogels make them excellent materials for specific therapeutic applications such as oral drug administration, ocular route, nasal route, and transdermal route [9].

Hydrogels have the potential ability in oral drug delivery in particular for the delivery of macromolecules and hydrophilic drug molecules [10]. Hence the application of hydrogels has been extended to the treatment of patients with cancer and diabetics. In oral drug delivery, the drug is delivered to the following specific sites: mouth, stomach, small intestine, and colon. Hydrogels with mucoadhesive ability are mainly used for this application (**Figure 2**) [9].

Nowadays the significance of protein and peptide drugs is increasing due to their potent action and high selectivity but the vital problem arises due to the enzymatic activity in the GI tract that results in the degradation of these drugs. However, studies have shown that hydrogels equip a platform that aids to deliver the drugs to specific sites in the GI tract and thus have significant importance in the delivery of protein and peptide drugs through the GI tract [10]. Crosslinked hydrogels can be used to

#### **Figure 2.**

*(a) The drug-containing component is coated with a hydrogel membrane and, the drug concentration is greater in the center of the system, allowing for a constant rate of release in the reservoir delivery system; and (b) Matrix delivery allows for uniform drug dissolution or dispersion across the hydrogels 3D structure (adapted from [8]).*

#### **Figure 3.**

*Illustration of drug level in the blood with repeated dosing (solid line) and controlled delivery dosing (dotted line) (adapted with permission from [10]).*

safeguard drugs from detrimental conditions including low pH in the stomach and enzymes due to the crosslinked nature of networks. Controlled diffusion of watersoluble drugs is possible in the hydrogel network. The density and chemical structure of the crosslinking agent determines mesh size [10]. An illustration of drug levels in the bloodstream is shown in **Figure 3**.

Another type of hydrogel called stimuli-responsive hydrogel is considered a potential substance for oral drug delivery. The peculiarities of stimuli-responsive hydrogel include the capability to respond to the changes in the environment, permeability, swelling nature, and ability to control drugs. The major objective of controlled drug delivery is to maintain a stable concentration of dose in the blood which cannot be achieved through a traditional drug release mechanism [10].

The field of eye treatment is currently employing the characteristics of hydrogels to treat the health problems such as blinking, tear drainage, and low permeability of the cornea, and the method is known as ocular route drug delivery [9].

The transdermal route of administration is another way of using hydrogels in drug delivery. This method helps to avoid drug degradation, side effects, and aids in maintaining a steady drug release. It is important to note that in comparison with conventional ointments water holding hydrogels can provide a better feeling to the skin hence this is highly preferred [9].

In reality, designing and synthesizing environmentally sensitive hydrogels offers a lot of potential in healthcare and nanotechnology applications in the future. The creation of advanced materials that can specifically address applications in biomedical issues is important to the achievement of these materials. This progress will be made through the introduction of unique polymers or the modification of existing polymers.
