Optimization and fabrication of dissolvable microneedle arrays for glucosamine, chondroitin, and hyaluronic acid for osteoarthritis treatment

Official URL: https://risc01.sabanciuniv.edu/record=b2766810_(Table of contents)

Due to their various advantages compared to conventional drug delivery systems such as hypodermic injections and oral medications, microneedle arrays (MNAs) is a promising drug delivery system. Needle geometry is an important parameter to achieve enhanced performance of the MNA. Thus, it is crucial to develop numerical models and optimize the needle geometry. In this work, a multi-objective optimization framework is presented to determine the optimum design of MNAs. For this purpose, a three-dimensional model of a single microneedle (MN) is developed. To simulate the insertion process, a load is applied at the tip region. Since depending on the orientation of the force, the failure can be either due to the buckling or bending, a multi-objective optimization based on non-dominated sorting genetic algorithm II (NSGA-II) is performed to obtain geometrical properties such as needle width, tip (apex) angle, base fillet radius. The objective is to prevent mechanical failure when the needles are inserted into the skin; thus the objective function is set to minimize the maximum stress occurring throughout the structure. As a result, the chosen dimensions provides a safety factor of 8.8. Based on the optimized geometry of the needles, master molds for MNAs are then fabricated from PMMA using mechanical micromachining process. This fabrication method is selected mainly due to the geometry capability, production speed, production cost, and the variety of materials that can be used. These fabricated master molds are used repeatedly to fabricate Polydimethylsiloxane (PDMS) production (female) molds through microiv molding approach. In this study, the materials utilized in fabrication of MNAs are mainly considered for the application purpose of Osteoarthritis (OA), which is a degenerative chronic disorder, not only affecting the articular cartilage, but also the subchondral bone, synovium, joint capsule, and soft tissues around the joint. The main purpose of OA treatment is to preserve the structure and functions of the joint, reduce inflammation and fibrosis, and prevent progressive cartilage loss. Medical support therapies including glucosaminoglycan (GAG), chondroitin (CS), and hyaluronic acid (HA), are among the regenerative strategies to prevent surgical joint replacement. However, they must be taken orally in high doses, continuously and for weeks to months causing series of side effects in the gastrointestinal system. Therefore, to prevent these side effects by using MNAs to apply the desired therapeutic substances locally under the skin at the targeted dose preventing the hepatic first pass effect. Ultimately, a dissolvable polymer with the stated bioactive cargo is cast into the production molds under vacuum to produce the dissolvable MNAs. To characterize and demonstrate the performance of the fabricated needles, (i) scanning electron microscope images are taken which show the accuracy of the fabricated geometries with a 0.75%-0.80% difference from the targeted dimensions, and (ii) a series of in-vitro tests are performed including piercing, cytotoxicity, dissolution, scratch assay and HPLC. It is shown that optimized MN geometries can be precisely fabricated using the presented fabrication methodology and the fabricated MNAs have promising results regarding drug delivery and mechanical feasibility.