POLYMERIC MICRONEEDLES FOR TRANSDERMAL DRUG DELIVERY

Ph.DDOCTOR OF PHILOSOPH

Potential of biodegradable microneedles as a transdermal delivery vehicle for lidocaine

There has been an increasing interest in applying biotechnology in formulating and characterising new and innovative drug delivery methods, e.g., drug-loaded biodegradable microneedles within the area of transdermal delivery technology. Recently, microneedles have been proposed for use in pain management, e.g., post-operative pain management through delivery of a local anaesthetic, namely, lidocaine. Lidocaine is a fairly common, marketed prescription-based, local anaesthetic pharmaceutical, applied for relieving localised pain and lidocaineloaded microneedles have been explored. The purpose of this review is to evaluate the properties of biodegradable polymers that may allow the preparation of microneedle systems, methods of preparing them and pharmacokinetic conditions in considering the potential use of lidocaine for delivery through the skin

A compendium of current developments on polysaccharide and protein-based microneedles

Microneedles (MNs), i.e. minimally invasive three-dimensional microstructures that penetrate the stratum corneum inducing relatively little or no pain, have been studied as appealing therapeutic vehicles for transdermal drug delivery. Over the last years, the fabrication of MNs using biopolymers, such as polysaccharides and proteins, has sparked the imagination of scientists due to their recognized biocompatibility, biodegradability, ease of fabrication and sustainable character. Owing to their wide range of functional groups, polysaccharides and proteins enable the design and preparation of materials with tunable properties and functionalities. Therefore, these biopolymer-based MNs take a revolutionary step offering great potential not only in drug administration, but also in sensing and response to physiological stimuli. In this review, a critical and comprehensive overview of the polysaccharides and proteins employed in the design and engineering of MNs will be given. The strategies adopted for their preparation, their advantages and disadvantages will be also detailed. In addition, the potential and challenges of using these matrices to deliver drugs, vaccines and other molecules will be discussed. Finally, this appraisal ends with a perspective on the possibilities and challenges in research and development of polysaccharide and protein MNs, envisioning the future advances and clinical translation of these platforms as the next generation of drug delivery systems.publishe

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

Dissolving microneedles for cutaneous drug and vaccine delivery

Currently, biopharmaceuticals including vaccines, proteins, and DNA are delivered almost exclusively through the parenteral route using hypodermic needles. However, injection by hypodermic needles generates pain and causes bleeding. Disposal of these needles also produces biohazardous sharp waste. An alternative delivery tool called microneedles may solve these issues. Microneedles are micron-size needles that deliver drugs or biopharmaceuticals into skin by creating tiny channels in the skin. This thesis focuses on dissolving microneedles in which the needle tips dissolve and release the encapsulated drug or vaccine upon insertion. The project aimed to (i) design and optimize dissolving microneedles for efficient drug and vaccine delivery to the skin, (ii) maintain vaccine stability over long-term storage, and (iii) immunize animals using vaccine encapsulated microneedles. The results showed that influenza vaccine encapsulated in microneedles was more thermally stable than unprocessed vaccine solution over prolonged periods of storage time. In addition, mice immunized with microneedles containing influenza vaccine offered full protection against lethal influenza virus infection. As a result, we envision the newly developed dissolving microneedle system can be a safe, patient compliant, easy to-use and self-administered method for rapid drug and vaccine delivery to the skin.Ph.D.Committee Chair: Prausnitz, Mark; Committee Member: Compans, Richard; Committee Member: Milam, Valeria; Committee Member: Murthy, Niren; Committee Member: Weniger, Bruc

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

Novel procedures for the production of multi-compartmental biodegradable polymeric Microneedles

The aim of this work is a new stamp based method to fabricate multi-compartmental polymeric microneedles containing a model drug

Optimization of square microneedle arrays for increasing drug permeability in skin

Microneedles array is a new transdermal drug delivery technique designed to create holes in the epidermis and penetrate the stratum corneum, thus avoiding the high resistance of this barrier. Microneedles have been shown to increase the skin permeability of drugs with no or little pain. However, the skin permeability of epidermis while using microneedle arrays has yet to be fully studied. In some cases, microneedle and microneedle array designs which were developed based on certain criteria (e.g., material of the microneedles) have to be related to other criteria (e.g., drug permeability in skin, skin thickness, etc.). Therefore, in order to determine the optimum design of the microneedle arrays, the effect of different factors (e.g., number of the microneedle, surface area of the patch, etc.) along with skin permeability by using microneedles should be determined accurately. In this work, an optimization framework for transdermal delivery of high molecular weight drug from microneedle is presented. The outputs of this framework have allowed us to identify the optimum design of various microneedles. Data from this optimization algorithm is then used to predict skin permeability of high molecular weight injected into the skin from a microneedle system. The effect of the optimized microneedles on blood drug concentration has been determined. The outcome of this study is useful to propose an optimum design based on different measurement (e.g., variation of skin thickness) for transdermal delivery of drugs

Transdermal drug delivery by coated microneedles : geometry effects on effective skin thickness and drug permeability

Although transdermal drug delivery has been used for about three decades, the range of therapeutics that are administered this way is limited by the barrier function of the stratum corneum (the top layer of skin). Microneedle arrays have been shown to increase the drug permeability in skin by several orders of magnitude by bypassing the stratum corneum. This 15 can potentially allow the transdermal delivery of many medicaments including large macromolecules that typically cannot diffuse through the skin. This paper addresses the use of microneedles coated with a drug solution film. In particular, we identify how the geometries of various microneedles affect the drug permeability in skin. Effective skin permeability is calculated for a range of microneedle shapes and dimensions in order to identify the most 20 efficient geometry. To calculate effective permeability (Peff), the effective skin thickness (Heff) is calculated. These are then plotted for insulin as a model drug to see how various microneedle parameters affect the profiles of both Heff and Peff. It is found that the depth of penetration from the microneedle array is the most important factor in determining Peff, followed by the microneedle spacings. Other parameters such as microneedle diameter and 25 coating depth are less significant

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