8.5.3.1　Developmental history of MNs

MNs is an emerging minimally invasive TDD technology，which includes solid MNs，hollow MNs，coated MNs，soluble MNs，swellable MNs（also known as hydrogel MNs or phase-transition MNs），etc.MNs can deliver drugs through the formation of micron-level holes in the skin，improving the efficiency of drug penetration.In 1998，the research team of Dr.Prausnitz of the Georgia Institute of Technology in the United States applied reactive ion etching technology to fabricate a solid MNs array using silicon as the host material，with the length of about 150μm and a tip curvature radius of less than 1 μm.Later，they used this MNs array to conduct a skin penetration test for the first time.The results showed that the application of MNs can increase the percutaneous drug penetration rate of calcein（model drug）by 1000 times.Since then，solid MNs have developed rapidly，and a variety of MNs using metal，silica，glass，nickel，and titanium as host materials have shown up.In particular，in the cosmetic field，all kinds of commercial MNs have been extensively used.The application of solid roller MNs has been included in the 2016 edition of the Photodynamic Guidelines of the American Academy of Dermatology as a means of promoting penetration of photosensitizers in photodynamic therapy.However，solid MNs rely on two steps of“needle sticking and drug application”，which are troublesome to operate.Moreover，the drug dosage is difficult to control and the repeated use of the needle is prone to infection risks.Therefore，coated MNs and hollow MNs are evolved on the basis of solid MNs.The coated MNs smear drugs on the surface of the solid MNs，and drugs can be dissolved and diffused after MNs piercing into the skin，thereby achieving one-step administration and significantly improving the efficiency of drug utilization.Macroflux（produced by Zosano Pharm），which was approved by the US FDA in 2002，is the earliest approved MN device and a typical representative of coated MNs.Nonetheless，coated MNs also face challenges such as small drug loading.Hollow MNs are micron-level matrix syringes，the typical representative of which is Micronjet（produced by NanoPass Technologies）approved by the US FDA in 2009.Most of the above three categories of MNs are made of metal，ceramics，glass or silicon，so they generally are poorly biocompatible，easy to leave needle tips and call for professional involvement.In recent years，the advent of soluble MNs and swellable MNs based on biomedical polymers has overcome these deficiencies.Soluble MNs dissolve subsequent to penetrating into the skin，achieving the one-step administration.Furthermore，they have relatively high drug loading and excellent tissue compatibility.Additionally，they are quite cost-effective and can be operated by patients without leaving sharp needles.The swellable MNs swell and release drugs after contacting with the tissue fluid in the skin.After drugs are released，the MNs can be pulled out to prevent the polymer from depositing in the skin.Since the swellable MNs absorb tissue fluid，they can also be used for skin tissue fluid extraction.

Production strategies of polymer MNs include micro-molding（MM），hot embossing（HE），drip blow molding（DAB），electrographic drawing（ED），injection molding（IM），laser micromachining（LMM），drawing lithography（DL），lithography（PL），overmolding（IM），continuous liquid interface production（CLIP），dipping，solvent casting，X-ray and 3D printing.The appropriate production method should be selected according to the category of MNs，host materials and drug properties.For example，the process of swellable MNs synthesis often requires high temperature or UV，so the potential impact of the corresponding generation process on drugs should be considered.(https://www.daowen.com)

This section focuses on the application of biomedical polymers as the host materials of coated MNs，soluble MNs and swellable MNs in skin diseases，because biomedical polymers have only a few applications in solid MNs and hollow MNs，and its advantages are less obvious compared to other materials.