**3.1 Oral route**

Oral administration currently is the most common and convenient for hydrogel drug delivery systems, thanks to their bioavailability and nontoxicity they provide [67, 68].

#### **Figure 3.**

*In-vivo hydrogel-based drug delivery in most common routes of administration. The schematic illustration is reproduced from [59].*


#### **Table 1.**

*Types of hydrogel-based products applied via different routes of drug administration [10, 59].*

However, such systems have limitations due to the metabolic effect these systems have on the living organism including but not limited to denaturation and reduction of epithelial membrane permeability [52]. Delivery systems in this strategy are usually made from caprolactone, MPEG, itaconic acid pH-sensitive hydrogels as they were reported to have no signs of toxicity [68].

## **3.2 Rectal route**

This route provides an alternative to intravenous and subcutaneous medication delivery. It has faster absorption of the medication through rectum's blood vessels, which makes it ideal for therapeutics that have high bioavailability and shorter duration [69, 70]. Moreover, it provides a stable environment in which the drugs are released since this administration strategy bypasses the gastrointestinal tract. As a result, minimal alterations occur to the drug concentration when it reaches the circulation system [71]. Hydrogel-based delivery systems such as catechol-chitosan gels have shown excellent biocompatibility and were reported to have no toxicity in-vitro and in-vivo [54, 72].

#### **3.3 Subcutaneous route**

This route is very common in studies that involve animal models when developing gel-based injectable biomaterials such as alginate [73], gelatin [74], poly-acrylamide [75], ellagic acid [76], and pectin [77]. While these biomaterials have shown no toxic response when deployed in-vivo into the animal model, the majority of the studies have reported inflammatory effect due to the vascularized nature of the subcutaneous region that is associated with reactions against foreign moieties [78].

#### **3.4 Transdermal route**

In topical delivery, the therapeutics reach the circulation system through penetrating the skin layers; the drug passes through the startum corneum to deeper epidermis and dermis until it is absorbed by the dermal microcirculation [79, 80]. The hydrophilic nature of hydrogels allows them to hold considerable amounts of fluid content that ranges between 10% to 1000 times gels' dry weight [81], which makes them ideal for carrying drugs such as insulin, theophylline, sodium fluoride, and progesterone and heparin. Transdermal hydrogel patches can provide a controlled rate of drug delivery in addition to providing a cooling effect at the location where they are applied [81]. Hydrogels can also be combined with bio-adhesives to prolong the therapeutic effect of the delivered drug when applied topically [82].
