Fabrication of a polymeric microneedle array for the decalcification of blood vessels

Abstract

Blood tissue calcification involves the deposition of calcium and phosphate minerals, predominantly within blood vessel walls, impacting cardiovascular health. Blood vessel calcification remains a significant concern in cardiovascular health, contributing to various complications such as medial arterial calcification (MAC) and intimal atherosclerotic calcification. While traditional treatment options have limitations, emerging research suggests that ethylenediaminetetraacetic acid (EDTA) could serve as a promising chelating agent to reverse calcification. When delivered in close proximity to the calcification site, EDTA has shown potential for mitigating calcification progression and restoring vascular function. This study aimed to develop a dissolvable polymeric microneedle (MN) array to be loaded with EDTA to treat vascular calcification in a site specific manner. Two MN formulations were prepared, the first from a combination of chitosan, polyvinyl alcohol and hydroxypropyl cellulose and the second from a cross-linked sodium alginate solution using a mould-based method. EDTA was successfully loaded into both MN formulations for further evaluation. Chitosan MN arrays were loaded with 340 μg of EDTA while alginate arrays were loaded with 965.8 μg of EDTA. The arrays were analysed by, differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) spectroscopy and Fourier transform infrared (FTIR) spectroscopy. The morphological features and mechanical strength, were investigated by scanning electron microscopy and texture analysis respectively. The fabricated arrays were of 8 mm x 8mm patch size containing 10 x 10 needles. Each needle has a length of 300 μm, needle base of 100μm and needle pitch of 500μm. It was shown that MN arrays were mechanically sufficiently strong to penetrate the vascular tissue. The typical failure force ranged from 0.338 to 0.345 Newton per needle for chitosan and alginate MN arrays respectively. Chitosan MN arrays achieved a 315 μg release within 24 hours while alginate arrays released 789 μg in the same period. Drug permeation studies were carried out on porcine venous tissue and showed in enhanced permeation ability of the alginate arrays after 6 hours. The MN arrays also both showed good hemocompatibility via hemolysis testing, with no significant increase in hemolysis and calcium chelating ability based on the quantity of EDTA permeating the tissue layer. Overall, this study resulted in the successful preparation of two dissolvable, EDTA loaded MN arrays from natural polymers using a simple, mould-based method. These MNs were found to penetrate the vascular tissue with minimal application forces and release bioactive over a 24 hour period. These polymeric MNs could prove useful for the delivery of many other drugs to the vascular system which would benefit therapeutic outcomes of patients greatly.