NEW INNOVATIVE IMPLANTABLE DEVICES FOR CONTROLLED DRUG DELIVERY

Abstract

This dissertation focuses on the design, development and evaluation of implantable drug delivery devices that can replace frequent injections and oral administrations with single implantation and maximize the therapeutic effect of chronic diseases. Currently, implantable drug delivery devices have been widely developed and used in clinical practice, but there are still a number of limitations. Therefore, I propose new innovative implantable drug delivery devices based on a new operating principle. First, I developed a microchannel-based implantable microchip that can be pre-programmed prior to implantation and released in a self-controlled manner after implantation. The key of this study is that the device can control the desired amount of drug release by adjusting channel dimensions (i.e., cross-sectional area (A) and length (L)) based on the Diffusion flux and Fick's first law of diffusion equation. The microchip was made of poly(methyl methacrylate), where a pair of micro-channels and micro-wells was embedded to serve as a drug diffusion barrier and a reservoir, respectively. Micro-channel can be precisely fabricated by controlling the CO2 laser output, processing speed, and irradiation height. To achieve both almost immediate onset and continuous release of DS, a single microchip equipped with the micro-channels with A/Ls of 0.0280 mm, 0.0217 mm and 0.0108 mm was prepared and exhibited continuous drug release for 70 days (almost zero-order pattern for 31 days, R2 > 0.996). When the resulting microchip was implanted in living rats, the drug concentration in the blood could be maintained at 148 ng/ml–225 ng/ml for the first 30 days while showing good biocompatibility. In addition, I also designed an implantable battery-less device enabled with patient-driven, on-demand insulin release to be actuated by an externally applied magnetic field. The key of this study is that the device can be operated without battery. So just apply a magnetic field on the skin instead of an injection needle, the exact amount of drug can be delivered. Unlike other active implantable drug delivery devices where an internal battery is required, MDP does not require a battery. Therefore, it is small in size and does not require re-surgery, so it can be used semi-permanently. To demonstrate in vivo feasibility, it was proved that the insulin concentration and decreased glucose level in the STZ-induced diabetes rat model were maintained at 741.8 ± 4.13 µUml-1 and 300.3 ± 10.8 mg dl-1, respectively in the MDP group similar to the values of 683.3±16.9 µUml-1 and 251.1 ± 6.41mg dl-1 in the S.C injection group for 60 days. Through these studies, I envision that microchannel-based implantable microchip and implantable battery-less device can offer a patient-oriented new concept biomedical technology.