# State-of-All-the-Art and Prospective Hydrogel-Based Transdermal Drug Delivery Systems
## 4 Skin and Diffusion through the Skin
### Methods of Enhancing Drug Penetration
#### 4.3.1 Active Methods for Permeation Enhancement  
Despite its merits, transdermal drug delivery is significantly hindered by the notable limitation that the skin's permeability to most molecules, except for a select few that are small and hydrophobic, is remarkably low [61]. Consequently, achieving a therapeutically relevant rate of drug delivery across the skin proves challenging [61]. Employing external stimuli such as electrical, physical, or mechanical forces can enhance the skin permeability of drugs and biomolecules in transdermal drug delivery [62]. The physical methods for enhancement of skin permeation include iontophoresis, electroporation, sonophoresis, microneedles, etc.  
channel [68]. Photomechanical waves can be generated by direct or confined ablation, resulting in two different characteristics [69]. [PERSON] et al. investigated how pulse characteristics influence the depth of penetration of macromolecules delivered into the skin through photomechanical waves generated by a Q-switched ruby laser [69]. The study revealed that controlled ablation, as opposed to direct ablation, produces photomechanical waves with longer rise times and durations. To achieve greater penetration depth, controlled ablation requires low radiant exposure. Customizing the characteristics of photomechanical waves is essential for achieving effective transdermal drug delivery, as they directly impact the depth of drug penetration into the skin, especially the dermis. Ablation is induced by these waves with exposure to incident waves ranging from 5 to 7 J/cm\({}^{2}\) at a depth of 50-400 \(\upmu\)m for successful transmission.  
The microneedle drug delivery system comprises hypodermic needles and transdermal patches. Micron-sized needles, referred to as M.N.s, can establish microchannels in the skin to facilitate drug delivery by disrupting the stratum corneum [56]. Moreover, they are less invasive and induce less pain compared to hypodermic needles, as they do not reach the pain receptors located in the dermis layer [70]. Based on fabrication methods, microneedles (M.N.s) can be categorized as solid, hollow, polymer, coated, dissolving, and hydrogen-forming M.N.s [56]. The solid microneedle delivers the drug by penetrating the skin at the patch placement site. Drug-coated microneedles are inserted into the skin, releasing the coated drug within the skin. Biodegradable or polymeric microneedles encapsulating drugs are inserted into the skin to accomplish controlled drug release. Hollow microneedles are employed to house naturally delivered melting needles. Hydrogel-forming microneedle arrays enable the transdermal delivery of drugs by piercing the outer layer of the skin surface and absorbing interstitial skin fluid along with inflammatory processes [71]. The microneedle drug delivery system comprises microneedles with heights ranging from 50 to 900 \(\upmu\)m, enabling them to penetrate deep into the skin and easily traverse the stratum corneum barrier [72]. In a conducted study [73], hydrogel-forming microneedles (HFMs) were employed for the transdermal delivery of albendazole from liquid reservoirs. The findings suggested that HFMs could penetrate up to 63% into the skin with only a 7.14% reduction in height.  
Thermal ablation is a method for selectively altering the stratum corneum structure by applying localized heat, enhancing drug delivery through microchannels formed in the skin [13]. Thermal ablation can be achieved by applying moderate temperatures (\(\leq\)100 \({}^{\circ}\)C) for a longer period or by applying very high temperatures (\(\geq\)100 \({}^{\circ}\)C) for a short period [74]. The second method is more favorable as it causes less damage to the skin. Thermal ablation can be achieved using various modes such as chemical heating, thermoporation, radio frequency (R.F.), and laser [74].