Design and Development of Novel Polymeric Microneedle (MN) arrays for MN Characterization, Biomarker Diagnosis and Drug Delivery

• Main Author: Zayim Razina Seeni Syed
• Other Authors: Xu Chenjie
• Format: Theses and Dissertations
• Language: English
• Published: 2019
• Subjects: DRNTU::Engineering::Bioengineering
• Online Access: https://hdl.handle.net/10356/106504; http://hdl.handle.net/10220/48101
• Institution: Nanyang Technological University

Advances in microtechnology and biomedical imaging technology has led to extensive research for self-administered and minimally-invasive microneedle (MN) devices to overcome drawbacks of existing transdermal drug delivery modalities. Microneedle mediated drug delivery is an amalgam of the conventional transdermal patch and the hypodermic needle injection. This novel drug delivery method increases the permeability of skin by piercing the stratum corneum barrier to create transient micropores through which drug molecules can passively diffuse. Furthermore, MN treatment is relatively painless and well tolerated by most patients, making it a very realistic technique for clinical implementation. In the first generation of microneedles (MNs), materials such as silicon, stainless steel, titanium and ceramics have been widely used in MN fabrication. However, several drawbacks such as poor biocompatibility, breakage in skin and need for expensive microelectronics technology for fabrication exists. In the contrary, polymeric MNs have attracted extensive attention due to their excellent biocompatibility and biodegradability. Most importantly, different types of polymers display distinct degradation profiles and swelling properties which can be potentially leveraged upon to fabricate polymeric MNs with different mechanical properties and performance. Polymeric MNs have shown to be ideal candidates for both transdermal drug delivery (TDD) and skin interstitial fluid (ISF) extraction. Water-soluble and biodegradable polymers have been used in the fabrication of MNs to achieve different drug release profiles such as bolus or sustained drug release. Swellable MNs fabricated using hydrogel-forming polymers have been investigated for its potential in ISF extraction for clinical biomarker diagnosis. Hence, with the promising outlook of polymer based MN technology this thesis work aims to broaden the scope of existing polymeric MN design and drive the development of novel polymer based MN arrays for clinical applications. In this thesis, polymers are used in the development of novel MN arrays for transdermal drug delivery and ISF extraction. Specifically, a conductive MN for in situ combination with iontophoresis (ITP) is fabricated for directional and fast transdermal drug delivery in a one-step approach. Most of the current polymeric MN platforms rely on passive diffusion driven concentration gradients to facilitate drug movement from the epidermis into the deeper layers of the skin; delaying the onset of drug effect. The use of conductive and biocompatible polymers; poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) polymer and hyaluronic acid (HA) in the design of the MN array results in aqueous pathways of low electrical resistance to be created in skin resulting in faster flow rate of drug molecules. This approach offers a new strategy for non-invasive and controlled delivery of drug molecules into deeper tissues underlying the epidermis to result in quicker systemic effect. Next, a proof-of-concept for a polymer MN-based minimally invasive glucose sensor that can extract ISF and provide colorimetric detection of glucose in a single step is described. Prepared using a poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) swellable tip and non-swellable polystyrene core, the MN tips are encapsulated with an assay solution that qualitatively produces a color change from colourless to purple in the presence of glucose. This process is achieved within minutes as it leverages on the polymer properties of the MN tips; it is made up of poly(acrylic acid) polymer which contains ionizable carboxylic acid groups that allow sufficient extraction of ISF. The color change observed on the MN tips is easily correlated to the glucose concentration and quantified using an ultraviolet–visible spectrophotometer (UV-VIS). Thus, this work strongly illustrates the potential of using the swellable polymeric MN array for quick determination of glycaemic conditions for patients requiring frequent monitoring. Aside from the development of novel polymeric MN arrays, imaging tools for characterization of MN behaviours such as dissolution and swellability was studied in detail. Current techniques of characterization include mostly in vitro and histological studies. The cumbersome and destructive nature of these studies results in poor accuracy and do not permit real time visualization of MN behaviours in skin. For the first time, optical resolution-photoacoustic microscopy (OR-PAM) is shown to be capable of achieving real time and in vivo monitoring of the spatial distribution of gold nanoparticles (AuNPs) in mice skin when delivered using poly(methyl methacrylate) (PMMA) MNs. Although optical coherence tomography (OCT) imaging has been widely used in MN imaging, poor backscattering ability of polymers results in low resolution images that require post image processing. Taking this into account, a methodology is developed to use iron oxide (Fe3O4) nanoparticles as exogenous contrast agents to enhance image contrast in OCT imaging and shown to enable high resolution and real-time visualization of changes in the profile of poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) MNs when inserted into different types of tissues i.e mice skin and human skin. In the future, the imaging techniques can be applied for optimization of MN design parameters and real time visualization of drug release and ISF extraction to optimize device design.