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Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage., The effectiveness of influenza vaccination is limited by the quality and breadth of the immune response and the time required for vaccine delivery (1). Traditional intramuscular (i.m.) injection requires hypodermic [...]

Administration of protein and DNA biotherapeutics is limited by the need for hypodermic injection. Use of micron-scale needles to deliver drugs in a minimally invasive manner provides an attractive alternative, but application of this approach is limited by the need for suitable microneedle designs and fabrication methods. To address this need, this paper presents a conical polymer microneedle design that is fabricated using a novel integrated lens technique and analyzed for its ability to insert into the skin without mechanical failure. Microneedle master structures were fabricated using microlenses etched into a glass substrate that focused light through SU-8 negative epoxy resist to produce sharply tapered structures. Microneedle replicates were fabricated out of biodegradable polymers by micromoiding. Because microneedle mechanical properties are critical to their insertion into the skin, we theoretically modeled two failure modes (axial mode and transverse mode), and analytical models were compared with measured data showing general agreement. Guided by this analysis, polymer microneedles were designed and demonstrated to insert to different depths into porcine skin in vitro. 'Long' polymer microneedles were also demonstrated in human subjects to insert deeply without failure. Index Terms--Biodegradable polymer, lens, microneedle, transdermal drug delivery.

The goal of this study was to design, fabricate, and test arrays of hollow microneedles for minimally invasive and continuous delivery of insulin in vivo. As a simple, robust fabrication method suitable for inexpensive mass production, we developed a modified-LIGA process to micromachine molds out of polyethylene terephthalate using an ultraviolet laser, coated those molds with nickel by electrodepostion onto a sputter-deposited seed layer, and released the resulting metal microneedle arrays by selectively etching the polymer mold. Mechanical testing showed that these microneedles were sufficiently strong to pierce living skin without breaking. Arrays containing 16 microneedles measuring 500 [micro]m in length with a 75 [micro]m tip diameter were then inserted into the skin of anesthetized, diabetic, hairless rats. Insulin delivery through microneedles caused blood glucose levels to drop steadily to 47% of pretreatment values over a 4-h insulin delivery period and were then approximately constant over a 4-h postdelivery monitoring period. Direct measurement of plasma insulin levels showed a peak value of 0.43 ng/ml. Together, these data suggest that microneedles can be fabricated and used for in vivo insulin delivery. Index Terms--Drug delivery systems, laser machining, micro-machining.

Although biological effects of ultrasound must be avoided for safe diagnostic applications, ultrasound's ability to disrupt cell membranes has attracted interest as a method to facilitate drug and gene delivery. This paper seeks to develop 'prediction rules' for predicting the degree of cell membrane disruption based on specified ultrasound parameters and measured acoustic signals. Three techniques for generating prediction rules (regression analysis, classification trees and discriminant analysis) are applied to data obtained from a sequence of experiments on bovine red blood cells. For each experiment, the data consist of four ultrasound parameters, acoustic measurements at 400 frequencies, and a measure of cell membrane disruption. To avoid over-training, various combinations of the 404 predictor variables are used when applying the rule generation methods. The results indicate that the variable combination consisting of ultrasound exposure time and acoustic signals measured at the driving frequency and its higher harmonics yields the best rule for all three rule generation methods. The methods used for deriving the prediction rules are broadly applicable, and could be used to develop prediciton rules in other scenarios involving different cell types or tissues. These rules and the methods used to derive them could be used for real-time feedback about ultrasound's biological effects. Index Terms--Discriminant analysis, drug delivery, machine learning, prediction, ultrasound-mediated cell disruption.