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.

There is a rising need for inline sensors for continuous and non-destructive monitoring of crops status. As growth in agricultural productivity stagnates, farmers are increasingly adopting soil-implanted sensors that allow them to optimize their yields. In existing literature, plant bio-impedance has been shown to change accordingly with various biotic and abiotic stress factors, and thereby may constitute a marker of interest. Yet, to date, there is no widespread adoption of bio-impedance for plant health monitoring due to the low sensitivity of planar electrodes. This thesis is dedicated to the development of a plant impedimetric biosensor that utilizes micro-needles electrodes for enhanced sensitivity. The micro-needles have been designed to pierce the upper waxy layer (cuticle) of plants to measure impedance from the underlying layers. Moreover, a micromolding process has been utilized to fabricate the micro-needles at scale without sacrificing fidelity. The molds were fabricated using dip-in laser lithography to benefit from the high resolution and flexibility of the technique. Standard metal sputtering processes were then used to confer conductivity onto the micro-needles. Several micro-needle aspect ratios and geometries were explored and adapted for use on Barley (Hordeum vulgare L,) and Date Palm (Phoenix dactylifera). In order to assess the performance of the sensors, the impedance of several plant specimens was monitored using the developed sensors alongside planar electrodes. The impedance measured by the sensors was lower than that reported by planar electrodes at low frequencies, indicating successful bypassing of the cuticle, as desired. No adverse effects were observed on the plant tissue post micro-needle attachment for seven days. Furthermore, a cyclical diurnal pattern of impedance was observed in both plants that was entrained by light. Finally, the micromolding technique developed in this thesis can help produce high- fidelity 3D electrodes for bio-impedance monitoring. Once the mold is fabricated, the electrodes can be produced at scale without the need of clean-room equipment. Furthermore, the fabricated sensors can monitor bio-impedance of plant specimens for extended durations of time and may offer a platform that can be functionalized to selectively quantify specific phytohormones of interest.

Microneedle (MN)-based technologies are currently one of the most innovative approaches that are being extensively investigated for transdermal delivery of low molecular weight drugs, biotherapeutic agents and vaccines. Extensive research reports, describing the fabrication and applications of different types of MNs, can be readily found in the literature. Effective characterization tools to evaluate the quality and performance of the MNs as well as for determination of the dimensional and kinetic properties of the microchannels created in the skin, are an essential and critical part of MN-based research. This review paper provides a comprehensive account of all such tools and techniques.

No description available.

No description available.

Microneedles are a minimally invasive method for delivering drugs through the impermeable skin layers, and have been used to deliver a variety of compounds including macromolecules, vaccines, and naltrexone. Microneedles can be applied to the skin once, creating micropores that allow for drug delivery into the underlying circulation from a drug formulation. The utility of this technique, however, is blunted by rapid micropore closure. This research project sought to: 1) characterize micropore lifetime and re-sealing kinetics, and 2) prolong micropore lifetime via inhibition of the skin’s barrier restoration processes. Impedance spectroscopy was used as a surrogate technique in animals and humans to measure micropore formation and lifetime. A proof of concept study in humans, using impedance spectroscopy, demonstrated that diclofenac (a topical anti-inflammatory) applied to microporated skin resulted in slower re-sealing kinetics compared to placebo, in agreement with previous animal studies. The clinical feasibility of prolonging micropore lifetime with diclofenac was confirmed via 7-day delivery of naltrexone through microneedle treated skin in humans (compared to 72 hour delivery with placebo). Lastly, naltrexone gels with calcium salts were applied to microneedle treated skin (hairless guinea pigs) to restore the altered epidermal calcium gradient; this method did not significantly extend micropore lifetime.

Microneedle (MN) enhanced drug delivery is a safe, effective and efficient enhancement method for delivery of drug molecules across the skin. The “poke (press) and patch” approach employs solid stainless steel MN to permeablize the skin prior to application of a regular drug patch over the treated area. It has been previously shown that MN can be used to deliver naltrexone (NTX) at a rate that provides plasma concentrations in the lower end of the therapeutic range in humans. The drug delivery potential of this technique is, however, limited by the re-sealing of the micropores in a 48-72h timeframe. The goal of the current research was to optimize the formulation for a 7 day MN enhanced delivery system for NTX either by adding a second active pharmacological moiety or by optimizing formulation characteristics alone. Three different formulation strategies were explored: formulation pH optimization with NTX; a codrug approach with NTX and a nonspecific cyclooxygenase inhibitor, diclofenac (DIC); and a topical/transdermal approach with NTX and an enzyme inhibitor of the cholesterol synthesis pathway, fluvastatin (FLU). The results indicated that formulation pH cannot be used to extend micropore lifetime, although formulation optimization leads to enhanced transport and thus drug delivery across MN treated skin. The codrug approach was successful in extending the micropore lifetime and further screening of codrug structures and formulation optimization helped in selection of a codrug candidate suitable for evaluation in animal pharmacokinetic studies. Local treatment with FLU helped to keep the micropores open and enabled delivery of NTX for an extended period. The pores re-sealed on removal of treatment within a 30-45 minute timeframe, indicating that infection/irritation should not be a major issue, as in the case of other topical chemical enhancers. Thus, overall it can be concluded that different formulation strategies can be utilized to extend micropore lifetime and enhance delivery of drug molecules across the skin.

The objective of this research is to develop a three-dimensional (3-D) microfluidic/ electronic interface system for sustaining and monitoring 3-D neuronal networks. This research work is divided into two parts. One is the development of a 3-D multi-electrode array (MEA) with integrated microfluidic channels. The other is a microneedle array with embedded microelectrodes and microfluidic channels. The 3-D MEA is composed of three elements that are essential for the development and monitoring of 3-D cultures of neurons. These components consist of scaffolds for cellular growth and structural stability, microfluidic channels for cell maintenance and chemical stimulation, and electrodes for electrical stimulation and recording. Two kinds of scaffold structures have been fabricated. The first scaffolding scheme employs a double exposure technique that embeds SU-8 towers into an SU-8 substrate. The second scaffolding mechanism introduces interconnects between towers for the purpose of mechanically supporting 3-D cell cultures and facilitating 3-D synaptic connections. Microfluidic channels are combined for fine control of the cellular microenvironment by means of diffusive and convective fluidic processes. Hollow towers with three-layer side ports were developed by using double exposure techniques and excimer laser ablation. The electrodes are combined into an integrated system that is capable of monitoring electrical activities and the cellular impedances of neurons which are attached to the electrodes. The second part of this research is to fabricate a microneedle array for monitoring brain slices, which will directly detect electrical signals from living brain slices. Although the microneedle array is targeting different 3-D neuronal networks, it also has three components and the fabrication steps are the same as those for the 3-D MEA. To generate the sharp tip, isotropic reactive ion etching (RIE) is performed on tapered SU-8 towers. High aspect ratio tower structures can be effectively generated with SU-8 and tapered shapes are created by backside exposure. The resulting systems will enable a new field of neurobiological research, in which the collective properties of 3-D neuronal circuits can be observed and manipulated with unprecedented detail and precision, and at a level of control not possible in living animals.

This thesis aimed to investigate and document the potential of applying ceramics in two specific drug delivery applications: tamper-resistant opioid formulations and transdermal enhancement protrusions. Geopolymers were developed into the matrix for a tamper-resistant formulation, aiming to protect drug substances from non-medical abuse. The synthesis conditions and excipients composition of the geopolymer-based formulation were modified in this work to facilitate a stable and extended drug delivery. Results showed that 37ºC 100% humidity for 48 hours were applicable conditions to obtain geopolymer with suitable mechanical strength and porosity. Moreover, it was found that the integration of poly(methyl acrylate) into the geopolymer-based formulation could reduce the drug release at low pH and, meanwhile, maintain the mechanical strength. Therefore, the geopolymer-based drug formulations concluded from these studies were applied in oral and transdermal delivery systems. Evidence of the tamper-resistance of geopolymer-based oral and transdermal formulations was documented and compared to the corresponding commercial opioid formulations. The results provided experimental support for the positive effects of geopolymers as drug carriers for the tamper-resistance of oral and transdermal delivery systems. Self-setting bioceramics, calcium phosphate and calcium sulfate were fabricated into transdermal enhancement protrusions in this work for the first time. Results showed that, under mild conditions, both bioceramics could form pyramid-shaped needles in the micron size. The drug release from these needles could be controlled by the bulk surface area, porosity and degradation of the bioceramics. An in vitro insertion test showed that the bioceramic microneedles had enough mechanical strength to insert into skin. Further optimization on the geometry of needles and the substrate material was also performed. The higher aspect-ratio needles with a flexible and self-swellable substrate could release most of the drug content within 4 hours and could penetrate through the stratum corneum by manual insertion. This study explored the potential application of bioceramics in transdermal enhancement protrusions and showed promising indication of their future developments.

Type-1 diabetes and influenza cause significant illness and unnecessary medical costs despite the existence of insulin for maintenance of diabetes and a vaccine for prevention of influenza. This dissertation describes three studies on the development and clinical translation of microneedles to improve the administration of these biopharmaceuticals. The first study reports on a sharp-tipped hollow metal microneedle designed to reduce manufacturing costs, improve insertion into skin, and improve fluid flow compared to other hollow microneedles used for drug delivery. The results showed sharp-tipped metal microneedles could be fabricated using an inexpensive electroplating and sacrificial micromolding process. Single-microneedle devices made by this method achieved high flow rates and delivered model drugs into tissue. The second study reports on insulin delivery using microneedles in children with type-1 diabetes. The results showed microneedle insertion was less painful, which is a promising result for improving injection compliance in children. Additionally, microneedle delivery showed rapid onset of insulin action compared to subcutaneous catheter delivery, which may enable automatic closed-loop insulin therapy. This was the first study of drug delivery to children using microneedles. The last study reports on microneedle patches for self-vaccination against influenza. Human subjects were recruited from greater Atlanta, were asked to self-administer placebo microneedle patches, and were then given a dynamic questionnaire to determine their views and preferences regarding influenza vaccination using microneedles compared to conventional intramuscular injection. The results showed that microneedles were usable by the participants, the introduction of microneedles may improve vaccination coverage by approximately 20%, and self-administration of vaccines may significantly reduce vaccination costs for a healthcare payer. This was the first study to assess the ability of human subjects to self- administer a microneedle patch and the first study to determine the potential impact of self-vaccination against influenza using a microneedle patch on vaccination coverage and vaccination cost. Overall, the fabrication advances and positive findings from human subjects research support additional translation of microneedles for insulin delivery and self-vaccination toward clinical use.