Microrobots for biomedical applications have various advantages such as minimally invasive surgery, targeted delivery of drug or biological compounds to specific area, as well as transportation energies, for example, thermal energy by hyperthermia treatment in comparison to a conventional invasive surgery. For such targeted therapeutics with microrobots, it is crucial not only to accurately control them but also to make them biocompatible to use in an in-vivo environment. In terms of the biocompatibility, biodegradable material has emerged as a promising material because it naturally biodegrades into harmless substances in aqueous environment therefore the microrobot does not need to be retrieved from the body. In this thesis, we developed 2 dimensional biodegradable microrobot for targeted drug delivery that consists of poly (D,L-lactide-co-glycolide acid) (PLGA), magnetic particles (Fe particles) (average size < 10 μm) and a drug compound, 5 Fluorouracil (5-FU). The microrobot was fabricated with various 2 dimensional shapes of water-dissoluble PVA templates cut by using UV laser micro machining. Most biomedical microrobots that uses photo-curable reagent to polymerize and form microrobot structure under UV require post-process to load drugs because drugs can be denatured by UV. In contrast, the developed biodegradable microrobot allows simultaneous encapsulation of anticancer drug (5-FU) without additional drug loading procedure, forming a microrobot structure in PLGA/Fe/5-FU solution. Translational and rotational motion of the developed 2 dimensional biodegradable microrobot were remotely and accurately controlled by external magnetic field (constant magnetic field (B) to Z axis and magnetic field gradient (∇B) to X axis) manipulated using an electromagnetic actuation (EMA) system. The fastest translational velocity of fabricated microrobot with 60 % (w/v) of magnetic particles was approximately 2.8 mm/s (≈1/5 body length per second). They have successfully loaded and released approximately 0.013 μg/microrobot of anticancer drug (5-FU) in aqueous environment (around pH 7, 37 ˚C) by biodegrading itself for 6 weeks. In conclusion, the facile fabrication was developed to form 2 dimensional biodegradable microrobot with various shapes using UV laser micro machining, encapsulating drugs into the microrobot simultaneously. The 2 dimensional biodegradable microrobot was successfully controlled by using electromagnetic actuation (EMA) system and released drugs for 6 weeks by biodegrading itself. ⓒ 2017 DGIST
Table Of Contents
1. INTRODUCTION 12-- 1.1 Background 12-- 1.2 Trend of research for targeted drug delivery 15-- 1.2.1 Trend of the microrobot 15-- 1.2.1.1 Bradley J. Nelson group 15-- 1.2.1.2 Joseph Wang group 18-- 1.2.1.3 Jong-Oh Park group 20-- 1.2.1.4 My group 22-- 1.2.2 Trend of the micro- and nano-particle 24-- 1.3 Aims of research 27-- 2. MATERIALS AND FABRICATION 29-- 2.1 Materials 29-- 2.1.1 Biodegradable polymer 31-- 2.1.2 Anticancer drug (5Fluorouracil) 33-- 2.1.3 Other materials 34-- 2.2 Fabrication 36-- 2.2.1 Preparation of poly (vinyl alcohol) thin film 39-- 2.2.2 Preparation of the PLGA solution with magnetic particles 39-- 2.2.3 Fabrication of the 2dimensional biodegradable microrobots with various shapes for targeted drug delivery 42-- 3. EXPERIMENTAL SETUP 45-- 3.1 UV laser micro machine 45-- 3.2 Electromagnetic actuation system 46-- 3.3 Optical microscope 47-- 3.4 Field emission scanning electron microscope 47-- 3.5 Fourier transform infrared spectroscopy 47-- 3.6 UV-VIS-NIR spectrophotometer 47-- 4. RESULTS AND DISCUSSIONS 48-- 4.1 Characterization of the 2dimensional biodegradable microrobot 48-- 4.1.1 Optical microscope images of the 2dimensional biodegradable microrobot 48-- 4.1.2 Chemical structure of the 2dimensional biodegradable microrobot 53-- 4.2. Movement of the 2dimensional biodegradable microrobot 56-- 4.2.1 Principles of translational and rotational motion of the fabricated 2dimensional biodegradable microrobot 56-- 4.2.2 Time-lapsed image of translational and rotational motion the fabricated 2dimensional biodegradable microrobot 59-- 4.2.3 Translational velocity of the fabricated 2dimensional biodegradable microrobot 63-- 4.3. Degradation of the fabricated 2dimensional biodegradable microrobot 66-- 4.3.1. Experimental procedure and degradation of the fabricated 2dimensional biodegradable microrobot 66-- 4.3.2 Relationship between the amount of poly (D,L-lactide-co-glycolide acid) and iron particles in fabricated 2dimensional biodegradable microrobot 73-- 4.4 Drug release from the fabricated 2dimensional biodegradable microrobot with anticancer drug (5Fluorouracil) 75-- 4.4.1 Experimental procedure and calibration curve of anticancer drug 75-- 4.4.2 Drug release from the fabricated 2dimensional biodegradable microrobot 78-- 4.5 Discussion 80-- 5. CONCLUSIONS 82