Abstract：Insulin, the only hormone in human body that decreases blood glucose, plays an important role in diabetes treatments. Currently, as a biopharmaceutics, it is mostly administrated by injections. Moreover, frequent dosing is required because of its short half-life, bringing great pain to patients.The transdermal drug delivery system is one of orientations, which can avoid enzymatic degradation caused by gastrointestinal absorption in noinvasive way. However, due to the skin barrier, it is difficult for insulin to pass through the skin to achieve therapeutic effects.Microneedle,a novel transdermal technology, can establish micron-scale drug delivery channels to corium layer, and enhance drug permeability especially macromolecular drugs. In recent years, more and more studies focus on microneedle technology to efficiently and safely transport insulin. Thus, we will briefly summarize the types of microneedles, and introduce the mechanism of smart insulin microneedle delivery systems which can respond to changes of blood glucose concentration.
SAHASRABUDHE R A, LIMAYE T Y, GOKHALE V S. Insulin injection site adverse effect in a type 1 diabetes patient: an unusual presentation. J Clin Diagn Res, 2017, 11(8):10-11.
[3]
CAO S J, XU S, WANG H M, et al. Nanoparticles: oral delivery for protein and peptide drugs. AAPS Pharm Sci Tech, 2019, 20(5):190.
[4]
WIEDERSBERG S, GUY R H. Transdermal drug delivery: 30+years of war and still fighting!. J Controlled Release, 2014, 190:150-156.
[5]
WAGHULE T, SINGHVI G, DUBEY S K, et al. Microneedles: a smart approach and increasing potential for transdermal drug delivery system. Biomed Pharmacother, 2019, 109:1249-1258.
[6]
K ITA. Transdermal delivery of drugs with microneedles-potential and challenges. Pharmaceutics, 2015, 7(3):90-105.
[7]
CHEUNG K, HAN T, DAS D B. Effect of force of microneedle insertion on the permeability of insulin in skin. J Diabetes Sci Technol, 2014, 8(3):444-452.
[8]
QIU Y, QIN G, ZHANG S, et al. Novel lyophilized hydrogel patches for convenient and effective administration of microneedle-mediated insulin delivery. Int J Pharm, 2012, 437(1-2):51-56.
[9]
TU J, DU G, NEJADNIK M R, et al. Mesoporous silica nanoparticle-coated microneedle arrays for intradermal antigen delivery. Pharm Res, 2017, 34(8):1693-1706.
[10]
GHOLAMI S, MOHEBI M M, HAJIZADEH-SAFFAR E, et al. Fabrication of microporous inorganic microneedles by centrifugal casting method for transdermal extraction and delivery. Int J Pharm, 2019, 558:299-310.
[11]
GUPTA J, FELNER E I, PRAUSNITZ M R. Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. Diabetes Technol Ther, 2009, 11(6):329-337.
[12]
MCVEY E, HIRSCH L, SUTTER D E, et al. Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal microneedle or subcutaneous infusion. J Diabetes Sci Technol, 2012, 6(4):743-754.
[13]
RESNIK D, MOŽEK M, PECAR B, et al. In vivo experimental study of noninvasive insulin microinjection through hollow Si microneedle array. Micromachines (Basel), 2018, 9(1):40.
[14]
YANG S, WU F, LIU J, et al. Phase-transition microneedle patches for efficient and accurate transdermal delivery of insulin. Adv Funct Mater, 2015, 25(29):4633-4641.
[15]
SEONG K Y, SEO M S, HWANG D Y, et al. A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin. J Controlled Release, 2017, 265:48-56.
[16]
JIN X, ZHU D D, CHEN B Z, et al. Insulin delivery systems combined with microneedle technology. Adv Drug Deliv Rev, 2018, 127:119-137.
[17]
CHEN B Z, ASHFAQ M, ZHANG X P, et al. In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery. J Drug Target, 2018, 26(8):720-729.
[18]
MOFFATT K, WANG Y, RAJ SINGH T R, et al. Microneedles for enhanced transdermal and intraocular drug delivery. Curr Opin Pharmacol, 2017, 36:14-21.
[19]
KHETAN S, GUVENDIREN M, LEGANT W R, et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat Mater, 2013, 12(5):458-465.
[20]
YU W, JIANG G, ZHANG Y, et al. Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin. Mater Sci Eng C Mater Biol Appl, 2017, 80:187-196.
[21]
LIU D, YU B, JIANG G, et al. Fabrication of composite microneedles integrated with insulin-loaded CaCO3 microparticles and PVP for transdermal delivery in diabetic rats. Mater Sci Eng C Mater Biol Appl, 2018, 90:180-188.
[22]
CHEN C H, SHYU V B, CHEN C T. Dissolving microneedle patches for transdermal insulin delivery in diabetic mice: potential for clinical applications. Materials, 2018, 11(9).
[23]
PODUAL K, DOYLE F J, PEPPAS N A. Glucose-sensitivity of glucose oxidase-containing cationic copolymer hydrogels having poly(ethylene glycol) grafts. J Controlled Release, 2000, 67(1):9-17.
[24]
CHEN G, YU J, GU Z. Glucose-Responsive microneedle patches for diabetes treatment. J Diabetes Sci Technol, 2019, 13(1):41-48.
[25]
CHOU D H, WEBBER M J, TANG B C, et al. Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates. Proc Natl Acad Sci USA, 2015, 112(8):2401-2406.
[26]
GU Z, DANG T T, MA M, et al. Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. ACS Nano, 2013, 7(8):6758-6766.
[27]
YU J, ZHANG Y, YE Y, et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc Natl Acad Sci USA, 2015, 112(27):8260-8265.
[28]
YU J, ZHANG Y, GU Z. Glucose-responsive insulin delivery by microneedle-array patches loaded with hypoxia-sensitive vesicles. Methods Mol Biol, 2017, 1570:251-259.
[29]
YE Y, YU J, WANG C, et al. Microneedles integrated with pancreatic cells and synthetic glucose-signal amplifiers for smart insulin delivery. Adv Mater, 2016, 28(16):3115-3121.
[30]
SARAVANAKUMAR G, KIM J, KIM W J. Reactive-oxygen-species-responsive drug delivery systems: promises and challenges. Adv Sci, 2017, 4(1), 1600124.
[31]
HU X, YU J, QIAN C, et al. H2O2-Responsive vesicles integrated with transcutaneous patches for glucose-mediated insulin delivery. ACS nano, 2017, 11(1):613-620.
[32]
WANG J, YE Y, YU J, et al. Core-sell microneedle gel for self-regulated insulin delivery. ACS nano, 2018, 12(3):2466-2473.
[33]
VEISEH O, TANG B C, WHITEHEAD K A, et al. Managing diabetes with nanomedicine: challenges and opportunities. Nat Rev Drug Discov, 2015, 14(1):45-57.
[34]
ZHANG Y, WANG J, YU J, et al. Bioresponsive microneedles with a sheath structure for H2O2 and pH cascade-triggered Insulin Delivery. Small, 2018, 14(14):e1704181.
[35]
YU J, QIAN C, ZHANG Y, et al. Hypoxia and H2O2 dual-sensitive vesicles for enhanced glucose-responsive insulin delivery. Nano Lett, 2017, 17(2):733-739.
[36]
TONG Z, ZHOU J, ZHONG J, et al. Glucose- and H2O2-responsive polymeric vesicles integrated with microneedle patches for glucose-sensitive transcutaneous delivery of insulin in diabetic rats. ACS Appl Mater Interfaces, 2018, 10(23):20014-20024.
2020, Vol. 55 
