8.4.1.2 The second generation：non-invasive penetra...
The second generation of TDD technology focuses on two innovations.①It improves the transdermal ability of drugs with application of penetration enhancers or nano-drug carriers（e.g.，liposomes，microemulsions and gels）.②It uses thermal perforation（accelerating drug penetration and making the skin more permeable with the thermal energy），electroporation（using high voltage short electrical pulses to temporarily increase skin permeability），ionophoresis（using low voltage current to pass drugs through the skin），and non-cavitation ultrasound（relying on the mechanical and thermal effects of ultrasound to promote drug transdermal ability）and other external drives to reversibly improve the skin's permeability to drugs.The second generation of TDD technology only temporarily alters the skin's permeability to drugs without damaging the integrity of the skin structure and skin barrier function，which is safe and non-invasive.Nevertheless，the second generation of TDD technology still has its limitations.On the one hand，although the non-invasive penetration promotion method can improve the drug delivery efficiency to a certain extent，the overall bioavailability of drugs is still low.On the other hand，the rise of biologicals has brought new challenges to TDD（see extended reading 2）.From 2015 to 2018，nearly 30％of all drugs approved by the US FDA were biologicals.At present，the vast majority of biologicals are peptide scaffolds，of which more than 50 monoclonal antibodies have been approved and become critical treatments in clinical practice.Monoclonal antibodies of TNFα，IL-17A，IL-23 and IL-4/IL-13 have been widely used in various dermatological diseases such as psoriasis and atopic dermatitis.Biologicals have a large molecular weight（e.g.，a monoclonal antibody has about 500 amino acid residues with a molecular weight of about 150000）and poor stability.Therefore，it is difficult to meet the transdermal requirements of biologicals through the second generation of TDD technology.(https://www.daowen.com)