Wearable and functional microneedle skin patch platforms with 3D printing for transdermal drug delivery

• Main Author: Tay, Jie Hao
• Other Authors: Song Juha
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2022
• Subjects: Engineering::Bioengineering; Engineering::Chemical engineering::Polymers and polymer manufacture; Engineering::Mathematics and analysis::Simulations
• Online Access: https://hdl.handle.net/10356/163862
• Institution: Nanyang Technological University

Increasing needs of painless, self-administrable and readily available home healthcare applications have driven the advancement of transdermal drug delivery system (TDD), aiming to replace current therapeutic and health monitoring schemes that require physical attendance and sophisticated process. Microneedle (MN) technology as third generation TDD system has been exploited in many bio-functional applications such as transdermal drug delivery and biosensing due to its greater skin disruption in minimal invasive manner as compared to previous generations that have molecular size limit and with needs of external power supply. MN device is designed in patch form with a collection of microscale-needles attachment as this allows simultaneous breaching of skin barrier in wider area for drug delivery and biosensing purposes. An ideal MN system should allow consistent and uniform penetration over target skin region especially when human skin is curved at most body areas while viscoelastic in nature. MN patch that failed to conform effectively onto target site could lead to under-desired therapeutic outcome and poor signal recording. Moreover, current MN systems are designed for finger-pressing administration therefore often in miniatured size, limiting the adaptability for most protein and peptide delivery dosage. To date, these issues have not been addressed effectively, hindering global commercialization of MN technology. Inspired by brilliant evolution of ancient fish armour system which has shown co-existence of rigidity and flexibility, we have found that they possess great similarities with the ideal MN system from micro- to macroscale aspects. Therefore, in this thesis, I mainly focus on improvement on penetration efficiency of individual MN tips through 1) mechanical reinforcement at micro-scale (Chapter 3) and 2) adaptive tip configuration of flexible MN substrates depending on surface geometry at macro-scale (Chapter 4). Particularly, in this thesis, rapid dissolving biopolymer low molecular weight hyaluronic acid (HA) was used for dissolving MN (DMN) systems due to its high dissolution rates and abundant availability in human body naturally with reasonable drug loading capabilities. However, the degradable polymer-based MN systems often experience significantly reduced transdermal penetration, especially when polymers have intrinsically weak mechanical strength as compared to other non-biodegradable materials like metal. Therefore, first, an in situ precipitation of silica network in HA matrix was proposed to improve intrinsic mechanical strength and improved physiological stability during administration of MN patches. Silica is a widely used bioactive additive with rapid physiological decay rate. Optimization of silica content in HA matrix was first studied through structural characterization to ensure minimal morphological defects in fabricated MN. Moreover, chemical analyses were used to characterize micro-structure and distribution of silica network in HA matrix. The HA-Si MNs fabricated demonstrated improved penetration efficiency and slight effect on dissolution behavior to pure HA MNs. Moreover, no cytotoxicity was found in the optimized HA-Si sample, indicating that the proposed hybridization of bioactive additive was encouraging. Moreover, MN system comprises of tip region and base substrate where flexible and continuous base substrates have been proposed in previous studies to address skin conformity issue of traditional MN systems with rigid base substrate. However, existing flexible MN system only offers bidirectional flexibility, therefore not yet able to address conformity issues at movable joint regions like elbow. Furthermore, upscaling of MN patch dimension is expected in future market in order to resolve issue of limited drug loading and skin coverage for biosensing of wider body areas. Therefore, in this project, a kirigami-based auxetic fractal cut pattern was introduced into the flexible base substrate design, resembling that of wavy patterned fish tissue. Numerical and experimental evaluations have demonstrated significant improvement in terms of contact stability, complex skin geometry coverage, penetration depth and insulin delivery. These tests were designed and compared among traditional rigid, flexible continuous and proposed flexible fractal cut patch. Moreover, novel two-step fabrication of proposed fractal cut MN patch using DLP printing was accomplished with high precision, lower production time/cost and promising functionality by exploiting working principle of DLP printing. Finally, customizability of FF MN patch in terms of patch size, subunit shape design and heterogeneity of MN material-drug formulation were displayed and proven to be a promising platform for diverse biomedical applications. The two approaches presented in this thesis have shown to be the key aspects to consider when designing an ideal MN patch with excellent penetration efficiency, high drug loading and skin coverage, in micro- and macroscopic perspectives. With further development of such flexible MN system, MN technology will soon to be adopted in more therapeutic and biosensing applications, finally bringing revolution to the biomedical fields as a pain-free and multipurpose healthcare tool.