Dissolvable Microneedles for Drug Delivery, Biosensing, and Neural Probe Delivery: Characterization and Functional Applications

Biodissolvable microneedles have been the focus of much research during the last decade due to the exciting advantages they bring in drug delivery and neural probes. Enhanced transdermal and intradermal drug delivery can be realized by using dissolvable microneedle arrays (MNAs), which are minimally invasive devices that facilitate effectively bypassing the stratum corneum barrier of the skin. The biocargo (drugs, vaccines, viral vectors, proteins, etc.) is embedded in the dissolvable material during fabrication of the MNAs, and upon administration to the skin, MNAs dissolve and release the biocargo to the targeted

skin microenvironment. Delivery of ultra-miniature, ultra-compliant neural probes, which enable measuring action potentials from and providing stimulation to the nervous

system, can be achieved by utilizing dissolvable, high-aspect-ratio microneedles as probedelivery vehicles. During placement of the probe, the needle provides sufficient strength and stiffness, and subsequently dissolves away, leaving behind only the high-compliance neural probe.

Although biodissolvable microneedles offer attractive advantages, significant advances are needed to address critical challenges, ranging from the assessment of biocompatibility of dissolvable materials, to the selection of effective design parameters, and to the development

of effective manufacturing approaches. The overarching objective of this doctoral research is to address those challenges related to the assessment of biocompatibility and the characterization of insertion mechanics to identify favorable design parameters. Furthermore, two high-impact application of dissolvable MNAs for delivery of exosome-embedded therapeutics and of viral vectors are evaluated through a range of in vitro, ex vivo, and in vivo studies. The specific objectives of this PhD research are:

• A systematic investigation of the cytotoxicity of carbohydrate-based dissolvable polymers used for production of microneedles: For dissolvable microneedles to satisfy regulatory requirements and be utilized in clinical applications, it is critical to characterize the cytotoxicity of the dissolvable polymers thoroughly. To achieve this objective, five dissolvable materials, including carboxymethyl cellulose, maltodextrin, trehalose, glucose, and hyaluronic acid, were evaluated using in vitro cell culture methods on relevant mouse and human cells. Qualitative and quantitative analyses of cytotoxicity were performed using optical microscopy, confocal fluorescence microscopy, and flow cytometry-based assays for cell morphology, viability, necrosis and apoptosis.

• Characterization of forces during insertion of dissolvable neural-probe delivery microneedles into the brain: An experimental study was conducted to evaluate the effect of geometric parameters (i.e., needle shape, apex angle, tip radius, and cross-sectional area) and insertion speed on the insertion forces of neural-probe delivery microneedles to excised rat brain and a well-established tissue phantom, agarose. To accurately and reproducibly measure the insertion forces, a custom-made force measurement system was developed. Next, an analytical model was developed to model needle insertion forces, and the experimental data was utilized to identify the model parameters.

• Vibration-assisted insertion of microneedles: An experimental study was conducted to explore the application of mechanical vibration during insertion to assess its effects on microneedle insertion forces, including evaluation of vibration amplitude, vibration frequency, and insertion speed.

• Analysis of mechanics during MNA insertion to skin for identification of favorable insertion and MNA design parameters: An experimental study was conducted to evaluate the effect of geometric parameters (i.e., needle shape, apex angle, and interspacing), insertion speed, and skin biaxial stretching on the insertion forces during insertion of MNAs to freshly excised rat skin.

• Evaluation of functional and biological effectiveness of MNAs through novel applications: (a) Intradermal delivery of exosomes using dissolvable MNAs to control inflammation: Here, dissolvable MNAs were investigated as a system for localized delivery of curcumin-loaded exosomes, and their in vivo delivery performance was assessed using rat and mouse inflammation models. (b) In situ, endogenous cell based inflammation sensors through MNA-mediated delivery of viral vectors: The objective of this study was to develop and demonstrate in vivo a robust, noninvasive biosensor composed of virally-activated endogenous cutaneous cells for monitoring inflammation biomarkers in real-time.