Needle-free liquid jet injectors were invented >50 years ago for the delivery of proteins and vaccines. Despite their long history, needle-free liquid jet injectors are not commonly used as a result of frequent pain and bruising. We hypothesized that pain and bruising originate from the deep penetration of the jets and can potentially be addressed by minimizing the penetration depth of jets into the skin. However, current jet injectors are not designed to maintain shallow dermal penetration depths. Using a new strategy of jet injection, pulsed microjets, we report on delivery of protein drugs into the skin without deep penetration. The high velocity (v >100 m/s) of microjets allows their entry into the skin, whereas the small jet diameters (50 -100 m) and extremely small volumes (2-15 nanoliters) limit the penetration depth (Ϸ200 m).In vitro experiments confirmed quantitative delivery of molecules into human skin and in vivo experiments with rats confirmed the ability of pulsed microjets to deliver therapeutic doses of insulin across the skin. Pulsed microjet injectors could be used to deliver drugs for local as well as systemic applications without using needles.MEMS ͉ nanotechnology ͉ noninvasive ͉ piezoelectric ͉ transdermal

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Liquid jet injections employ a high-speed jet to puncture the skin and deliver drugs without the use of a needle. They have been used to deliver a number of macromolecules including vaccines and insulin, as well as small molecules, such as anesthetics and antibiotics. This article reviews liquid jet injectors with respect to their historical perspective, clinical applications, mechanisms and future prospects. An overview of the use of jet injectors for delivery of vaccines, insulin and growth hormones is presented. Particular attention is paid to the mechanistic understanding of jet injections, especially the dependence of jet penetration on parameters such as nozzle diameter, velocity and jet power. Finally, gaps in the current understanding are presented and suggestions for future research and development are made.

The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production.