Patch-based transdermal drug delivery offers a convenient way to administer drugs without the drawbacks of standard hypodermic injections relating to issues such as patient acceptability and injection safety. However, conventional transdermal drug delivery is limited to therapeutics where the drug can diffuse across the skin barrier. By using miniaturized needles, a pathway into the human body can be established which allow transport of macromolecular drugs such as insulins or vaccines. These microneedles only penetrate the outermost skin layers, superficial enough not to reach the nerve receptors of the lower skin. Thus, microneedle insertions are perceived as painless. The thesis presents research in the field of microneedle-based drug delivery with the specific aim of investigating a microneedle-based transdermal patch concept. To enable controllable drug infusion and still maintain an unobtrusive and easy-to-use, patch-like design, the system includes a small active dispenser mechanism. The dispenser is based on a novel thermal actuator consisting of highly expandable microspheres. When actuated, the microspheres expand into a liquid reservoir and, subsequently, dispense stored liquid through outlet holes. The microneedles are fabricated in monocrystalline silicon by Deep Reactive Ion Etching. The needles are organized in arrays situated on a chip. To allow active delivery, the microneedles are hollow with the needle bore-opening located on the side of the needle. This way, the needle can have a sharp and well-defined needle tip. A sharp needle is a further requirement to achieve microneedle insertion into skin by hand. The thesis presents fabrication and evaluation of both the microneedle structure and the transdermal patch as such. Issues such as penetration reliability, liquid delivery into the skin and microneedle packaging are discussed. The microneedle patch was also tested and studied in vivo for insulin delivery. Results show that intradermal administration with microneedles give rise to similar insulin concentration as standard subcutaneous delivery with the same dose rate. / QC 20100623

Several studies have reported beneficial effects of C-peptide supplementation in diabetic patients and animal models of insulinopenic diabetes. However, it is also established that good glycemic control is essential to minimize the risk of diabetes-induced complications. This thesis investigates potential mechanisms for the beneficial effect of C-peptide on glomerular hyperfiltration, and a novel, painless route of insulin administration. The results demonstrate that both C-peptide and its C-terminal penta-peptide sequence reduce the diabetes-induced glomerular hyperfiltration within an hour. The results also indicate that C-peptide possibly reduces diabetes-induced hyperfiltration via three different mechanisms: 1. Constriction of the afferent arteriole was demonstrated on isolated vessels from diabetic mice. 2. A net dilation of the efferent arteriole was evident in vivo. 3. Inhibition of the Na+/K+-ATPase was demonstrated in vivo in diabetic rats as well as in vitro on isolated proximal tubular cells from diabetic rats. All these mechanisms are known regulators of the net glomerular filtration pressure. The last part of this thesis demonstrates that intradermal administration with a newly developed patch-like microneedle device results in similar insulin concentration compared to standard subcutaneous delivery. These findings provide an insight for the beneficial effects of C-peptide on diabetic kidney function, and shows that this effect can be achieved by infusion of the C-terminal penta-peptide sequence alone. This thesis also presents a novel, painless alternative to insulin injections that is controllable, requires minimal training, and therefore presents several advantages compared to current standard therapy.

Cromolyn sodium (CS) has clinically shown to be an effective topical remedy for atopic dermatitis, however its physiochemical properties prevent efficient passive drug delivery beyond the outermost skin layer. This project aimed to optimize CS gel formulations and applications to improve drug delivery to the dermis of skin by examining various topical enhancement strategies. Oleic acid, salcaprozate sodium, and microneedles were investigated as enhancers for their effect on skin permeation of CS. In vitro permeation studies across dermatomed porcine ear skin tested CS gels to determine 24-hour drug permeation profiles and skin layer distribution of drug. Further, extraction method efficiency, the enhancement mechanism of salcaprozate sodium, and gel stability were investigated. It was concluded that microneedle pretreatment delivered the greatest amount of CS to the dermis using a 4% CS gel without chemical enhancement. These results provide a promising option for a commercially available topical treatment of atopic dermatitis.

Hydrogen peroxide and chlorine detection is critical for many biological and environmental applications. Hydrogen peroxide plays important roles in a variety of fields including plant physiology, medical, environmental and biochemical applications. Its role in plant defense and signal transduction, diseases such as Parkinson's and Alzhemier's, industrial processes such as disinfection and wastewater treatment and biochemical enzymatic reactions is critical. Given the gamut of areas that hydrogen peroxide is a key component of; its detection assumes great importance. Similarly chlorine has long been used as a disinfectant for making drinking water safe, but excessive chlorination is an environmental and health hazard in itself. In this work, micromachining techniques have been used to design, fabricate and test electrochemical sensors and microneedle structure that can be integrated for detection of hydrogen peroxide and free chlorine. A novel nanomaterial has been integrated with the hydrogen peroxide microsensor, which greatly increases the sensor lifetime and robustness. Miniaturization, low detection limits, high sensitivity and selectivity, as well as ease of fabrication are some of the other advantages of this work.

No description available.

The InsulPatch is a novel integrated patch-pump device used to deliver drugs, especially macromolecular drugs that are difficult to deliver through an oral pathway and that require transdermal delivery. The patch-pump is a promising replacement for conventional syringes and battery-powered pumps because it is slim, powerless, painless, and relatively inexpensive. The majority of this thesis focuses on the fabrication and testing of microfluidic devices for the delivery of insulin, which is a model drug that is widely used and needs to be delivered transdermally. In this thesis, we demonstrate the fabrication of the patch-pump, which includes an insect-mimetic microfluidic pump fabricated using photolithography and replica molding, and a microneedle array fabricated using 3D printing. The microfluidic pump is used to drive the fluid flow powered by pressurized air or the user’s pulse, and the microneedle array is used to inject the fluid through the skin painlessly. Using pressurized air-driven flow testing, we have tested the flow rate across microfluidic pumps of various flow channel widths over a range of physiologically relevant actuation frequencies and pressures. We have found that for the specific channel design we have been using, the flow rate generally positively correlates with the actuation pressure. For devices with wider flow channels, the flow rate generally negatively correlates with the actuation frequency, whereas the flow rate increases and then decreases with increasing actuation frequency for devices with narrower flow channels. This property of these devices is beneficial in insulin delivery because the demand for insulin is generally reduced in vigorous exercise (with elevated heart rate/actuation frequency) and increased in hypertension patients (with elevated blood/actuation pressure). A major future direction of the study is to test a wide range of device designs in a sample of human subjects by attaching the device onto the wrist and measuring the pulse-driven flow across the device. We can further change the channel design parameters of the device so that it will be ideal for insulin delivery. Using the ex vivo flow testing and human subject data, we can further tailor the device design to specific patients using a genetic algorithm-guided optimization based on the heart rate and blood pressure of the patient and the desired flow rate. We will also perform computational modeling using COMSOL Multiphysics to predict the flow across devices of different designs as well as to understand the physics behind the pulse-driven flow. Finally, a 3D-printed insulin reservoir will be incorporated into our patch-pump system for the storage of U-500 insulin. / M.S. / The InsulPatch is a slim, powerless device (“patch-pump”) that can be used to deliver drugs through the skin, especially designed for drugs that are difficult to deliver orally. The patch technology is a promising replacement for conventional injection using syringes and bulky battery-powered pumps. At this stage, the primary drug that our device aims to deliver is insulin, which generally needs to be delivered through the skin. In this thesis, we demonstrate how our patch-pump is made and how its performance is tested. The patch-pump has two parts: the microfluidic pump and the microneedle array. The microfluidic pump is fabricated using a technique called photolithography, in which a photosensitive polymer is selectively cured by UV light, and replica molding, in which the precursor of another polymer is poured on a mold and cured. The microneedle array is made using 3D printing and designed in such a way so that it can be readily connected to the microfluidic pump. The microfluidic pump is used to drive the fluid flow powered by the user’s pulse, and the microneedle array is used to inject the fluid through the skin painlessly. Through testing the flow across the microfluidic pump prototypes using pressurized air, we characterized the correlation between the flow rate of fluid across the device and parameters including the actuation pressure and frequency of the pressurized air as well as the width of the flow channel. Future directions of the study include testing the devices in human subjects to characterize pulse-driven flow across the devices, computational modeling of the devices, and further changes of the device design to optimize the performance of the device. We will also optimize the device design computationally to tailor the device design to specific diabetic patients. Finally, we will incorporate a 3D-printed insulin reservoir into our system for the storage of insulin solution. / Withhold all access to the ETD for 1 year / patent / I hereby certify that, if appropriate, I have obtained and submitted with my ETD a written permission statement from the ower(s) of each third part copyrighted matter to be included in my thesis or dissertation, allowing distribution as specified above. I certify that the version I submitted is the same as that approved by my advisory committee.

The hydraulic resistance characterization manuscript chronicles the early development of the hollow-core fiberoptic microneedle device (FMD). The study determined that for straight tubing with an inner bore of 150 ?m and a length greater than 50 mm long, Poiseuille's Law was shown to be accurate within 12% of experimental data for the pressure range of 69-517 kPa. Comparison between different needle design geometries indicated that tip diameters <55 ?m cause a significant increase in hydraulic resistance. Tubing length should be kept to a minimum and tip diameter should be kept above this threshold to reduce overall hydraulic resistance. The bladder treatment study describes the fabrication and testing of the FMD for treatment of invasive urothelial cell carcinomas (UCCs). Experiments investigating the fluid dispersal of single-walled carbon nanohorns (SWNHs) in the wall of inflated, healthy ex vivo bladders demonstrated that perfusion of 2 cm° on the bladder wall's surface can be achieved with a 5 minute infusion at 50 ?L/min. Irradiation of the SWNH perfused bladder wall tissue with a free space, 1064 nm laser at an irradiance of 0.95 W/cm° for 40 seconds yielded a 480% temperature increase relative to similar irradiation of a non-infused control. Co-delivery experiments demonstrated both SWNH and light delivery though a single hollow-core fiber to heat the bladder wall 33 °C with an irradiance of 400 W/cm°, demonstrating that the FMD can be used to achieve hyperthermia-based therapeutic effects via interstitial irradiation. / Master of Science

*1-Dimensional Advective-Diffusion Model in Porous Media Infusion of therapeutic agents into tissue is makes use of two mass transport modes: advective transport, and molecular diffusion. Bulk infusion into a 0.6% wt agarose phantom was modeled as an infinite, homogenous, and isotropic porous medium saturated with the same solvent used in the infused dye tracer. The source is assumed to be spherical and isotropic with constant flow rate and concentration. The Peclet numberdecreases with power function Pe = 15762t0.337 due to the decrease in mean dye-front pore velocity as V goes to Vfinal. Diffusive mass transport does not become significant during any relevent time period. *Arborizing Fiberoptic Microneedle Catheter We have developed an arborizing catheter that allows multiple slender fused-silica CED cannulae to be deployed within a target volume of the brain via a single needle tract, and tested it in a widely accepted tissue phantom. The arborizing catheter was constructed by bonding and encapsulating seven slender PEEK tubes in a radially symmetric bundle with a progressive helical angle along the length, then grinding a conicle tip where the helical angle is greatest. The catheter was tested by casting 0.6% wt agarose around the device with all needles deployed to a tip-to-tip distance of 4 mm. Phantom temperature was maintained at 26 ± 2°C. 5% wt Indigo Carmine dye was infused at a rate of 0.3 uL/min/needle for 4 hours. N=4 infusions showed a Vd/Vi of 139.774, with a standard deviation of 45.01. This is an order of magnitude greater than single-needle infusions under similar conditions [45]. The arborizer showed the additional benefit of arresting reflux propagating up the lengths of individual needles, which has historically been a weakness of single-needle CED catheter designs. *In Vivo Co-Delivery of Single Walled Carbon Nano-horns and Laser Light to Treat Human Transitional Cell Carcinoma of the Urinary Bladder in a Rodent Model Using a rodent model we explored a treatment method for Transitional Cell Carcinoma (TCC) in the urinary bladder in which Single Walled Carbon Nanohorn (SWNH) solution and 1064 nm laser light are delivered into tumorous tissue via a co-delivery Fiberoptic Microneedle Device (FMD). Preliminary treatment parameters were determined by injecting SWNH solutions with concentrations of 0 mg/mL, 0.17 mg/mL, or 0.255 mg/mL into ex vivo porcine skin and irradiating each for three minutes at laser powers of 500 mW, or 1000 mW. The combination with the greatest temperature increase without burning the tissue, 0.17 mg/mL at 1000 mW, was selected for the in vivo treatment. TCC tumors were induced in a rodent model by injecting a solution of 106 AY27 urothelial carcinoma cells into the lateral aspect of the left hind leg of young, female F344 rats. When tumors reached 5-10 mm3, rats were anesthitized and treated. SWNH solution was injected directly into the tumor and irradiated until the target temperature of 60degC was achieved. The rats were then recovered from anestesia and monitored for 7-14 days, at which point they were humanely sacrificed, and the tumors prepared for histological examination. Histological assessment of areas of FMD treatment correlated well with gross morphological appearance. Foci of tumor necrosis showed sharp (1-2 mm) delineation from areas of viable tumor (not treated) and normal tissue. We believe we have demonstrated the feasibility of using the FMD for treatment of urothelial carcinoma using an animal model of this disease, and are encouraged to continue development of this treatment and testing in larger animal models. / Master of Science

Yes / Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy of micro-injection moulded microneedles and its influence on drug delivery. Microneedles of polyether ether ketone and polycarbonate and have been manufactured using micro-injection moulding and samples from each production batch have been subsequently subjected to a range of plasma treatment. These samples were coated with bovine serum albumin to study the protein adsorption on these treated polymer surfaces. Sample surfaces structures, before and after treatment, were studied using atomic force microscope and surface energies have been obtained using contact angle measurement and calculated using the Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness of the microneedles resulting in better adsorption and release of BSA.

Yes / Polymeric hydrogels are a complex class of materials with one common feature—the ability to form three-dimensional networks capable of imbibing large amounts of water or biological fluids without being dissolved, acting as self-sustained containers for various purposes, including pharmaceutical and biomedical applications. Transdermal pharmaceutical microneedles are a pain-free drug delivery system that continues on the path to widespread adoption—regulatory guidelines are on the horizon, and investments in the field continue to grow annually. Recently, hydrogels have generated interest in the field of transdermal microneedles due to their tunable properties, allowing them to be exploited as delivery systems and extraction tools. As hydrogel microneedles are a new emerging technology, their fabrication faces various challenges that must be resolved for them to redeem themselves as a viable pharmaceutical option. This article discusses hydrogel microneedles from a material perspective, regardless of their mechanism of action. It cites the recent advances in their formulation, presents relevant fabrication and characterization methods, and discusses manufacturing and regulatory challenges facing these emerging technologies before their approval.