Microfabricated needles have the potential for inexpensive drug delivery without pain. The ability to deliver medication painlessly to patients will someday be not just hoped for but expected by the general public. The commercialization of this technology will also lead to other valuable technologies, such as systems that continually monitor and control insulin or other drugs in diabetic patients. This research presents fabrication procedures developed to produce pyramidal-shaped microneedles with microchannels that will allow for fluid delivery. The microchannels are etched into the substrate surface of a [100] silicon wafer using inductively coupled plasma etching. After the channel etch a layer of silicon nitride is deposited onto the inner walls of the microchannels and on the surface of the substrate. The nitride on the substrate surface provides the hard mask necessary to etch the microneedles, which are wet etched in a bath of potassium hydroxide (KOH). The selectivity of the KOH on [100] silicon is such that octagonal shaped pyramids are etched into the surface of the wafer. The pyramids are aligned with the previously etched microchannels to allow for needles with channels running through them. This research presents the first needles demonstrated with drug delivery channels running through the robust pyramidal needle shape. In addition to the microchannel/microneedle fabrication procedure, microchannels were developed with inner structures as a method of creating hydrophobic surfaces on the inner walls of the channels. It was found that the channels developed had far too much variability in the diameter to accurately create a measurable reduction in flow; however, a loss coefficient was calculated showing increased flow rates in hydrophobically coated microchannels when hydrophobic structures are incorporated into the channel design. It was also discovered that a hydrophobic coating, typically used to increase flow rates through a channel, can impede flow rate. There was no evidence found to suggest that hydrophobically coated microchannels of this size, with or without structures, will yield higher flow rates than non-coated microchannels.

Study Design: Controlled laboratory study. Objectives: To determine the time course of dexamethasone sodium phosphate (Dex-P) iontophoresis delivery to underlying tissues using microdialysis. Background: The efficacy of iontophoresis at delivering Dex-P through the skin is unknown in humans because of the lack of minimally invasive measurement techniques. Methods: Sixty-four healthy male participants (age = 24.4 ± 3.3 yrs, height = 71.8 ± 2.5 in, weight = 181.8 ± 26.1 lbs) were randomly assigned into one of six groups: 1) 1 mA current, 1 mm probes depth ; 2) 1 mA current, 4 mm probes depth; 3) 2 mA current, 1 mm probes depth; 4) 2 mA current, 4 mm probes depth; 5) in vivo retrodialysis; and 6) skin perfusion flowmetry. Microdialysis probes assess the combined recovery (Dextotal) of Dex-P, dexamethasone (Dex) and its metabolite. In vivo calibration of the microdialysis probes occurred via retrodialysis. Laser Doppler flowmetry assessed skin perfusion. Results: There was no difference of Dextotal between current intensities (P = 0.99) but a greater amount of Dextotal was recovered by the 1 mm probe (P < 0.0001) compared to the 4 mm probe. Peak means for the 1 and 2 mA at 1 mm were 10.8 ± 8.1 and 7.7 ± 5.5 μg/ml and at 4mm being 2.0 ± 0.8 and 1.3 ± 0.9 μg/ml, respectively. Skin perfusion rapidly increased during both current intensity treatments, but significantly decreased before the conclusion of the 1 mA treatment (P < 0.0001). Peak skin perfusion was 741.4 ± 408.7% and 711.6 ± 260.8% baseline for 1 and 2 mA intensities, respectively. Conclusion: Iontophoresis delivery of Dex-P was successful measured in vivo through human skin. Significant concentrations of Dextotal were found regardless of current intensity. Though current induced vasodilation occurred, it did not significantly affect the tissue accumulation of Dextotal.

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Approximately 14,500 people were killed in traffic crashes where the driver was legally intoxicated in 2005, constituting 33% of all traffic fatalities that year. While social efforts to reduce the number of traffic fatalities have shown to be moderately successful, alcohol has remained a factor in 40% of all traffic deaths over the past decade. Transdermal ethanol detection is a promising method that could prevent drunk driving if integrated into an ignition interlock system; potentially preventing 90 million drunk driving trips a year in the US. However, experimental data from previous research has shown significant time delays between alcohol ingestion and detection at the skin which makes real time estimation of blood alcohol concentration via skin measurement difficult. Using a validated model we studied the effects that body weight, metabolic rate and ethanol dose had on the time lag between the blood alcohol concentration and transdermal alcohol concentration. The dose of alcohol ingested was found to have the most significant effect on the skin alcohol lag time. Additionally, custom transdermal ethanol sensors were designed and fabricated and a pilot study on human subjects was conducted to determine if inexpensive transdermal ethanol sensors could be used to detect alcohol in drivers. / Master of Science

Yes / The effective disposal of medication and more specifically accidental exposure to fentanyl via transdermal patches has recently been highlighted in two key documents [1, 2]. Whilst the volume of unused medicines cost the NHS over £300 million every year [1], the volume of transdermal patch waste is unknown. There is a need for greater pharmacy intervention in the effective disposal of medicines to resolve issues such as hospital (re)-admissions, stockpiling leading to patient self–prescribing/dosing, and land and water pollution. The aim of this study was to examine transdermal patch disposal systems and practice amongst private sector care providers in the UK. This was part of a larger study focusing on transdermal patch application. / The full text will be available on permission from the publisher.

No / A novel approach for identifying synergistic mixtures of skin penetration enhancers promises to transform development of transdermal products, including patches.

This thesis first briefly mentions the characteristics of the skin and contains a review of current knowledge on the in vitro permeation testing of drugs through the skin. It describes the basic data about nerve agents and the possibilities of prophylaxis poisoning warfare agents focusing on preventive transdermal administration. The experimental work is focused on in vitro testing abilities oxime HI-6 and posibly other reactivators enzyme acetylcholinesterase penetrate through pig skin. Experiments were conducted in static diffusion cells Franz type. The amount of test substance leaked through the skin is determined in the sample of receptor fluid by HPLC. Keywords permeation in vitro; transdermal; pig skin; Franz cell; substance HI-6; antidota; nerve agents; acetylcholinesterase

Microneedles have been developed as a minimally invasive alternative to painful hypodermic needles to deliver modern biotherapeutics. Previously, several in-vitro and in-vivo animal studies have been conducted to show that microneedles increase skin permeability to a wide range of molecules that cannot cross the skin using conventional transdermal patches due to the skin's stratum corneum barrier. However, only a limited number of studies have been performed to study microneedle-based drug delivery in human subjects. Therefore, the objective of this study was to perform the first-in-humans microneedle studies to: a) characterize skin repair responses to solid microneedle insertion to determine the extent of increased skin permeability coupled with predictions of pharmacokinetics of drug delivered through premeabilized skin, b) determine the effect of hollow microneedle-based infusion parameters on flow conductivity of skin and pain and thereby identify barriers to fluid flow into the skin from hollow microneedles, c) assess the safety and efficacy of systemic therapeutic effects through measurement of pharmacokinetic parameters, pain and irritation for microneedle-based insulin delivery in type 1 diabetes subjects, and d) assess the safety and efficacy of local therapeutic effects though delivery of lidocaine to the skin. Results showed for the first time that solid microneedle-treated skin reseals rapidly (< 2 h) in the absence of occlusion whereas occluded skin reseals slowly (3-40 h) depending on microneedle geometry as determined by skin impedance measurements. Increased microneedle length, number, and cross-sectional area led to slower recovery kinetics in the presence of occlusion. This thesis also demonstrated that the flow conductivity of skin decreased as fluid was infused to the dermis through hollow microneedles due to the dense structure of the dermis. Microneedle retraction, low flow rates, and the addition of hyaluronidase helped increase flow conductivity. Microneedles were able to deliver 800 µl of saline to the dermis without causing significant pain. Further, microneedle-based insulin delivery in type 1 diabetes subjects revealed that microneedles provided faster pharmacokinetics and improved glycaemic control than conventional subcutaneous catheters. Lastly, microneedle-based lidocaine injection demonstrated that microneedles were less painful, as effective, and more preferred than hypodermic needles in anesthetizing clinically relevant areas.

This dissertation presents the development of electrically-powered, lamination-based microactuators for the realization of large arrays of high impulse and short duration micro-jets with potential applications in the field of micro-electro-mechanical systems (MEMS). Microactuators offer unique control opportunities by converting the input electrical or chemical energy stored in a propellant into useful mechanical energy. This small and precise control obtained can potentially be applied towards aerodynamic control and transdermal drug delivery applications. This thesis discusses the development of both chemical and physical microactuators and characterizes their performance with focus towards the feasibility of using them for a specific application. The development of electrically powered microactuators starts by fabricating an array of radially firing microactuators using lamination-based micro fabrication techniques that potentially enable batch fabrication at low cost. The microactuators developed in this thesis consist of three main parts: a micro chamber in which the propellant is stored; two electrode structures through which electrical energy is supplied to the propellant; and a micro nozzle through which the propellant or released gases from the propellant are expanded as a jet. The fabricated actuators are then integrated with MEMS-process-compatible propellants and optimized to produce rapid ignition of the propellant and generate a fluidic jet. This rapid ignition is achieved either by making the propellant itself conductive, thus, passing an electric current directly through the propellant; or by discharging an arc across the propellant by placing it between two closely spaced electrodes. The first concept is demonstrated with chemical microactuators for the application of projectile maneuvering and the second concept is demonstrated with physical microactuators for transdermal drug delivery application. For both the actuators, the propellant integrated microactuators are characterized for performance in terms of impulse delivered, thrust generated and duration of the jet. The experimentally achieved results are validated by comparing with results from theoretical modeling. Finally, the feasibility of using chemical microactuators for maneuvering the path of a 25 mm projectile spinning at 500 Hz is discussed and the feasibility of applying the physical microactuators for increasing skin's permeability to drug analog molecules is studied.