Microneedle Devices And Methods Of Manufacture And Use Thereof

Microneedle devices are provided for transport of molecules across tissue barriers and for use as microflameholders. In a preferred embodiment for transport across tissue, the microneedles are formed of a biodegradable polymer. Methods of making these devices, which can include hollow and/or porous microneedles, are also provided. A preferred method for making a microneedle includes forming a micromold having sidewalls which define the outer surface of the microneedle, electroplating the sidewalls to form the hollow microneedle, and then removing the micromold from the microneedle. In a preferred method of use, the microneedle device is used to deliver material into or across a biological barrier from chambers in connection with at least one of the microneedles. The device preferably further includes a means for controlling the flow of material through the microneedles. Representative examples of these means include the use of permeable membranes, fracturable impermeable membranes, valves, and pumps.Georgia Tech Research Corporatio

Fabrication of Silicon In-plane and Out-ofplane Microneedle Arrays for Transdermal Biological Fluid Extraction

This thesis presents research in the field of microelectromechanical systems and specifically in the area of microneedle-based transdermal skin fluid extraction and drug delivery. The objective of this thesis is to highlight the potential role of microneedles in achieving painless transdermal skin biofluid extraction and drug delivery of macromolecular drugs across the skin barrier. The work represents the design and fabrication of silicon out-of-plane and in-plane microneedles and an innovative double-side Deep Reactive Ion Etching (DRIE) approach was presented for producing hollow silicon microneedle arrays for transdermal biological fluid extraction. The solid silicon out-of-plane microneedles are fabricated from a single side polished wafer whereas the hollow out-of-plane microneedles are fabricated from a double side polished wafer to a shank height of 200-300 μm with 300 μm center-tocenter spacing. The single-step Bosch DRIE is performed for “in-plane” silicon microneedles to simultaneously etch the needle shaft (parallel to silicon substrate, etch through the wafer) and the narrow trenches as open capillary fluidic channels (partly etched into the wafer), taking advantage of the aspect-ratio dependent DRIE etching. Furthermore, the double-sided two stage DRIE is performed to etch the open trenches on the backside of wafer and then the needle shaft on the front side. The in-plane needles have the advantages of making long needles up to 2 mm. Moreover, the in vivo testing results are provided as well. In this thesis, different microfabrication techniques are investigated, developed, optimized, and applied in the fabrication process. The first chapter conveys an overview of nanotechnology, nano-/microfabrication and their role in medicine. The second chapter illustrates an introduction to transdermal drug delivery and extraction. Furthermore, the fundamental background of skin structure and interstitial fluid (ISF) is introduced as well. Device fabrication tools and techniques are shown in chapter three. The fourth chapter presents a detailed literature review of microneedles in terms of its general concepts, structures, materials and integrated fluidic system. Eventually, Chapter 5 introduces the details of our method to fabricate solid and hollow silicon microneedle arrays step by step. SEM images and in vivo testing results confirm that silicon microneedle both out-of-plane and in-plane arrays are not only sharp enough to penetrate the stratum corneum but also robust enough to extract ISF out of skin or to deliver drug

An Electrically Active Microneedle Electroporation Array for Intracellular Delivery of Biomolecules

The objective of this research is the development of an electrically active microneedle array that can deliver biomolecules such as DNA and drugs to epidermal cells by means of electroporation. Properly metallized microneedles could serve as microelectrodes essential for electroporation. Furthermore, the close needle-to-needle spacing of microneedle electrodes provides the advantage of utilizing reduced voltage, which is essential for safety as well as portable applications, while maintaining the large electric fields required for electroporation. Therefore, microneedle arrays can potentially be used as part of a minimally invasive, highly-localized electroporation system for cells in the epidermis layer of the skin. This research consists of three parts: development of the 3-D microfabrication technology to create the microneedle array, fabrication and characterization of the microneedle array, and the electroporation studies performed with the microneedle array. A 3-D fabrication process was developed to produce a microneedle array using an inclined UV exposure technique combined with micromolding technology, potentially enabling low cost mass-manufacture. The developed technology is also capable of fabricating 3-D microstructures of various heights using a single mask. The fabricated microneedle array was then tested to demonstrate its feasibility for through-skin electrical and mechanical functionality using a skin insertion test. It was found that the microneedles were able to penetrate skin without breakage. To study the electrical properties of the array, a finite element simulation was performed to examine the electric field distribution. From these simulation results, a predictive model was constructed to estimate the effective volume for electroporation. Finally, studies to determine hemoglobin release from bovine red blood cells (RBC) and the delivery of molecules such as calcein and bovine serum albumin (BSA) into human prostate cancer cells were used to verify the electrical functionality of this device. This work established that this device can be used to lyse RBC and to deliver molecules, e.g. calcein, into cells, thus supporting our contention that this metallized microneedle array can be used to perform electroporation at reduced voltage. Further studies to show efficacy in skin should now be performed.Ph.D.Committee Chair: Mark G. Allen; Committee Member: Mark R. Prausnitz; Committee Member: Oliver Brand; Committee Member: Pamela Bhatti; Committee Member: Shyh-Chiang She

Enhancement of Percutaneous Absorption on Skin by Plasma Drug Delivery Method

Transdermal drug delivery (TDD) is a painless method of low-dose drug delivery. The advantages and disadvantages of transdermal drug delivery methods are named and basic methods such as using chemical enhancers, iontophoresis and electrophoresis are introduced. One of the promising methods make use of plasma which is generated in atmospheric pressure mostly in volume or on surface dielectric barrier discharge (DBD) or in plasma jet. As the plasma produces various particles according to the used gas, UV radiation and heat, their effects on skin and barrier function are described. Improvement of transdermal drug delivery of hydrophilic drug galantamine hydrobromide (GaHBr) using microplasma electrode is introduced

Fabrication of Metal/Oxide Nanostructures by Anodization Processes for Biosensor, Drug Delivery and Supercapacitor Applications

This dissertation proposed to initiate the research into the fabrication of metal/oxide nanostructures by anodization process for biosensor, drug delivery and supercapacitor applications by producing different nanostructures which lead to the potential for various applications. This study focuses on the establishment of the knowledge and techniques necessary to perform metal/oxide nanostructures on biological and energy applications. This study will investigate: (1) the sensor and drug delivery applications of micro/nano structures; (2) novel processes to innovate anodic aluminum oxide nanotube template; (3) the supercapacitor applications of anodic titanium oxide. First, the extremely high surface area AAO coated microneedle and microneedle array can be developed as sensor and drug delivery devices. Due to the large surface area of the AAO, the film can absorb indicators to make it sensitive to testing targets. pH detection was demonstrated to show the sensing capability of the microneedle. Then, the microneedles were further built as an array by combining micromachining technique. The microneedle array provides a 3-D structure that possesses several hundred times more surface area and capacity than a traditional nanochannel template. Second, the nanoengineering process was conducted to innovate anodic aluminum oxide nanotube template. Guided anodization assisted by nanoimprint process formed AAO arrays that can be formed on controlled locations. More importantly, it shows the periodically ordered AAO array with different sizes of nanopores. With the improved AAO template, melting injection, electro/electroless deposition and sol-gel deposition were conducted to fabricate Ni nanowires/ TiO_(2) nanotubes, Ni/BaTiO_(3) core-shell nanotubes, and UHMWPE nanotubes. Third, various Ti-based alloys were anodized to form ordered nanotubes for supercapacitor application. Ti alloy oxide contains some porous layers which are not presented on TiO_(2) nanotube film. Thus, Ti alloys anodized oxide nanotubes have better supercapacitor behaviors than the conventional TiO_(2) nanotubes. However, a high surface area nanoporous Ti/TiO_(2) structure, which was fabricated by selective etching process, can accumulate large quantity of electrons and energy for supercapacitor needs. Additionally, nanoporous metals obtained by dealloying hold a unique combination of a highly conductive network and a bicontinuous open. The characteristics formed through dealloying also present a nice charge/discharge behavior and a good capacitance performance

Creation and Optimisation of Plasma Etch Processes for the Manufacture of Silicon Microstructures

Microneedles are an area of growing interest for applications in transdermal delivery. Small, minimally invasive medical or cosmetic devices, microneedles are intended to penetrate the skin’s outer protective layer (stratum corneum) to facilitate delivery of active formulations into the skin. Delivery of solution via microneedles has the benefits associated with hypodermic injection, i.e. avoiding the first-pass metabolism systems, with the added advantages of painless delivery and dose sparing from the reduced solution volumes required.Advancements in semiconductor processing technologies and equipment have enabled the creation of devices and structures that could not have been fabricated in the past. This is also true for the fabrication of microneedles, where previous manufacturing methods have relied on hazardous chemicals such as Hydrofluoric Acid and Potassium Hydroxide to create the sharp tip of the needle, required to reduce insertion force.In this thesis, the realisation of a hollow bevelled silicon microneedle fabricated using only plasma processing techniques is presented, providing a route to scalable manufacture of high-performance, sharp-tipped microneedles. The microneedle fabrication process consists of three main etch steps in the process flow to create hollow structures. For each of the Bevel, Bore, and Shaft processes the development and optimisation is detailed. Throughout the process development, several unexpected processing issues were encountered, including depth non-uniformity, “notching”, and “silicon grass”. Investigations have been performed to determine the root cause of each issue and fine-tune processes to optimise the final devices. A discussion of the process hardware is also presented, with reference to the benefits for each specific application process.Following development and optimisation of each individual process, the Bevel, Bore, and Shaft processes were integrated in the manufacturing flow to create the final hollow silicon microneedle device. Issues arising from the combination of the three processes have been investigated, resolved, and optimised. This includes the conception and execution of a novel process for the plasma smoothing of an angled silicon surface, which improved the quality of lithography on the non-planar bevel surface and minimised grass formation.Preliminary testing, undertaken to assess the suitability of these devices for transdermal use, included mechanical fracture force, skin penetration, and injection testing. The microneedles were found to be strong enough to remain intact during insertion, and demonstrate successful penetration and injection through the stratum corneum and into the deeper skin layers

Fabrication of Hollow Silicon Microneedle Arrays for Transdermal Biological Fluid Extraction

This thesis presents the research in the field of microelectromechanical systems with the specific aim of investigating a microneedle based transdermal skin fluid extraction concept. This work presents an innovative double-side Deep Reactive Ion Etching (DRIE) approach for producing hollow silicon microneedle arrays for transdermal biological fluid extraction. The microneedles are fabricated from a double side polished wafer to a shank height of 200-300 μm with 300 μm center-to-center spacing. Moreover, the in vivo testing results are provided as well. In this thesis, several microfabrication techniques are investigated, developed and applied in the fabrication process. The first chapter brings an overview of nano-/microfabrication and MEMS for biomedical applications (drug delivery and biofluid extraction). Furthermore, the fundamental background of skin structure and interstitial fluid (ISF) is introduced as well. The second chapter clearly illustrates three key techniques specifically employed in the microneedle fabrication process which are photolithography, wet etching and dry etching. The third chapter presents a detailed literature review of microneedles in terms of its general concepts, structures, materials and integrated fluidic system. Eventually, Chapter 4 introduces the details of our method to fabricate hollow silicon microneedle arrays step by step. SEM images and in vivo testing results confirm that hollow silicon microneedle arrays are not only sharp enough to penetrate the stratum corneum but also robust enough to extract ISF out of skin. Ongoing work will focus on the optimization of the assemble extraction apparatus and the capillary filling of the holes

Microneedles for Transdermal Biosensing: Current Picture and Future Direction

A novel trend is rapidly emerging in the use of microneedles, which are a miniaturized replica of hypodermic needles with length-scales of hundreds of micrometers, aimed at the transdermal biosensing of analytes of clinical interest, e.g., glucose, biomarkers, and others. Transdermal biosensing via microneedles offers remarkable opportunities for moving biosensing technol-ogies and biochips from research laboratories to real-fi eld applications, and envisages easy-to-use point-of-care microdevices with pain-free, minimally invasive, and minimal-training features that are very attractive for both devel-oped and emerging countries. In addition to this, microneedles for trans-dermal biosensing offer a unique possibility for the development of biochips provided with end-effectors for their interaction with the biological system under investigation. Direct and effi cient collection of the biological sample to be analyzed will then become feasible in situ at the same length-scale of the other biochip components by minimally trained personnel and in a minimally invasive fashion. This would eliminate the need for blood extraction using hypodermic needles and reduce, in turn, related problems, such as patient infections, sample contaminations, analysis artifacts, etc. The aim here is to provide a thorough and critical analysis of state-of-the-art developments in this novel research trend, and to bridge the gap between microneedles and biosensors