Hyung Jung Yoo

Microfabrication Methods for Biodegradable Polymeric Carriers for Drug Delivery System Applications: A Review

A drug delivery system is used for targeting drugs to specific cells. Various drug carriers, that also reduce the side effects of unbound drugs, have been introduced and commercialized in the pharmaceutical field. Among them, synthetic biodegradable polymers have received much attention attributed to their low toxicity, controllable biodegradation rates, manufacturability, and low costs. This paper reviews the salient characteristics of biodegradable polymers as drug carriers and their microfabrication methods. The reviewed microfabrication methods include laser micromachining, rapid prototyping, replication, emulsification, microfluidic fabrication, and X-ray-lithography-based methods. For these microfabrication methods, critical dimensions, feature variety, solvent compatibility, production throughput, and tooling requirements are also summarized.

Microelectrode array with integrated nanowire FET switches for high-resolution retinal prosthetic systems

In this paper, a novel microelectrode array integrated with nanowire field-effect transistor (FET) switches is developed for retinal prosthetic systems. Retinal prosthetic systems require many electrodes (generally more than several hundreds) and this paper presents a novel method of integrating silicon nanowire-FET switches with microelectrodes that can significantly reduce wiring complexity. Also, in order to fit the curvature of an eyeball, the silicon nanowire FETs are transferred to a flexible substrate. In order to demonstrate the concept of using FETs for switching collocated retinal microelectrodes, a microelectrode array with 32???32 pixels is fabricated, which has 1,024 microelectrodes. Using the FET switches in a two-dimensional array addressing configuration, 1,024 microelectrodes are addressed by only 64 lines (32 for scan and 32 for data), as compared to requiring 1,024 lines in the conventional one-to-one configuration. With the gate voltage of ?5?V, the threshold voltage, current on/off ratio, and on-resistance of the fabricated silicon nanowire-FET switch are ?0.4?V, 1???107, and 37?47?k?, respectively. The maximum allowable current injection limit of the silicon nanowire-FET switch integrated microelectrode is 44??A with a pulse duration of 1?ms. These results show an excellent potential for high-resolution retinal prosthetic systems.

Electrical characteristics of 2D and 3D microelectrodes for high-resolution retinal prostheses

In order to provide high quality visual information to patients who have implanted retinal prosthetic devices, the number of microelectrode should be large. As the number of microelectrode is increased, the dimension of the microelectrode is decreased, which in turn results in the increased interface impedance of microelectrode and decreased dynamic range of injection current. In addition, the reduced maximum limit of injection current may not be sufficiently large to stimulate the ganglion cells in a retina. In order to improve the trade-off envelope between number of microelectrode and current injection limit, a 3D microelectrode structure can be used as an alternative. From the advancement of microfabrication technology, the fabrication of highly-accurate 3D structures with small dimensions is possible. This paper presents a first comprehensive electrical characterization of 2D and 3D microelectrodes for high-resolution retinal prostheses. Microelectrodes which differ in shapes and diameters are analyzed. Their interface impedances and charge injection limits are quantitatively analyzed. This research can be used to define requirements for further retinal prosthetic device research.

Motility Control of Bacteria-Actuated Biodegradable Polymeric Microstructures by Selective Adhesion Methods

Certain bacteria have motility and can be made non-toxic, and using them for drug delivery has been proposed. For example, using bacteria with flagella motion in multiple spin actuators in drug delivery microrobots has been suggested. This paper investigates various adhesion enhancement methods for attaching bacteria on preferred surfaces of cubic polymeric microstructures to achieve the directional control of motion. Serratia marcescens which has an excellent swimming behavior and 50-μm sized cubic structures made of biodegradable poly-capro-lactone (PCL) are used. Three treatment methods are investigated and compared to the untreated control case. The first method is retarding bacterial attachments by coating certain surfaces with bovine serum albumin (BSA) which makes those surfaces anti-adherent to bacteria. The second and third methods are roughening the surfaces with X-ray irradiation and plasma respectively to purposely increase bacterial attachments on the roughened surfaces. The measured motilities of bacteria-tethered PCL microactuators are 1.40 μm/s for the BSA coating method, 0.82 μm/s for the X-ray irradiation, and 3.89 μm/s for the plasma treatment method. Therefore, among the methods investigated in the paper the plasma treatment method achieves the highest directionality control of bacteria motility.

Drug-loaded cubic micro-chamber made of a biodegradable polymer for bacteria-based drug delivery

In this paper, a novel method of fabricating a drug-loaded, cubic micro-chamber made of biodegradable polymer for bacteria-based drug delivery is presented. A biodegradable polymer, poly-capro-lactone (PCL), is used to fabricate the micro-structure. The biocompatibility of PCL is approved by the Food and Drug Administration in U.S. for use in humans. To fabricate the drug-loaded cubic micro-chamber, laminated PCL films are prepared, and a drug is encapsulated between the films using the inkjet printing method. Generally, PCL cannot easy be micromachined by a conventional photolithography technique. Therefore, an x-ray lithography process is developed to fabricate the cubic structure. The fabrication results indicate that the proposed method is excellent for microfabricating drug-loaded cubic micro-chambers made of the biodegradable PCL polymer for bacteria-based drug delivery.

Mechanical and electrical evaluation for the long-term stability of implanted 3D retinal microelectrode

In this paper, the mechanical and electrical characteristics of 3D microelectrode are presented to provide the long-term stability of the implanted microelectrode. As the dimensions of the microelectrode become smaller, the microelectrode can be easily damaged by mechanical pressure and over-injected electric charge. In order to avoid these destructions, allowable mechanical and electrical stress should be determined. Experiments for durability evaluation are set up and performed to measure the mechanical force and safe charge injection limit. The result of the experiments shows that the allowable mechanical force in vertical and horizontal direction is 0.8165 N and 0.2068 N, respectively. In the charge injection test, it is observed that the density of injected charge is a prior factor in microelectrode dissolution rather than the total amount of injected charge.

Evaluation of Lapatinib Powder-Entrapped Biodegradable Polymeric Microstructures Fabricated by X-Ray Lithography for a Targeted and Sustained Drug Delivery System

An oral medication of a molecular targeted drug, lapatinib, is taken regularly to maintain the drug concentration within the desired therapeutic levels. To alleviate the need for such cumbersome administration schedules in several drugs, advanced drug delivery systems (DDSs), which can provide time-controlled and sustained drug release, have recently received significant attention. A biodegradable synthetic polymer, such as polycaprolactone (PCL), is usually used as a carrier material for DDSs. In this paper, lapatinib powder-entrapped, PCL microstructures were fabricated with a precise X-ray lithography-based method. In vitro experiments on HER2 positive-human gastric cancer derived NCI-N87 cells were performed to appraise the drug release characteristics of the fabricated DDSs. The in vitro results indicate that after the X-ray lithography process, the lapatinib powder is still working well and show time- and dose- dependent drug release efficiencies. The cell growth inhibition characteristics of one hundred 40-μm sized microstructures were similar to those of a 1 μM lapatinib solution for over 144 h. In conclusion, the developed lapatinib-entrapped PCL microstructures can be used in molecular targeted delivery and sustained release as effective cancer-targeted DDSs.

Bacteria-based microrobot for chemotaxis delivery

We proposed a simple microfluidic device that enabled anisotropic absorption of detoxified S.typhimurium bacteria to microcubics so that the particles can swim toward desirable direction by chemotaxis of the bacteria. The speed of the “bacteria-based microrobot” was ~5um/sec which is faster than any prior demonstrations, leading to an effective drug delivery system.

Surface energy modification method using x-ray synchrotron irradiation for controlling bacterial adhesion on biodegradable-polymer structures for bacteria-flagellated microrobots

Bacteria-based biomedical microrobots have been proposed to achieve effective localized drug delivery. To enhance a directional locomotion of bacteria-attached microsystem, structures with selective bacterial adhesion are necessary. Having different surface morphologies of microstructures is beneficial for selective attachments of bacteria. In this paper, a surface energy modification method for controlling bacterial adhesion on biodegradable-polymer structures is presented. This is achieved by controlling exposed doses of x-ray synchrotron irradiation. To calculate the x-ray exposure time for varying the surface morphology of the biodegradable polymeric devices, the equation for exposed dose is derived. The contact angles of different surfaces are measured, and the corresponding surface energies are calculated to verify the modification of the surface morphology. As a result, the surface energy increases with the increment of the exposed dose to the biodegradable-polymer. The developed surface energy modification method is suitable for modifying the polymeric surface without additional physical/chemical treatments. The fabricated cubic structures with different surface morphologies can be used for effectively flagellating bacteria on selective surfaces for directional locomotion.

Anisotropic bacterial adsorbed micro chambers by microfluidic trapping array

Bacteria based biomedical micro-robot is being investigated or proposed to achieve effective and localized drug delivery system due to low toxicity and free of external power sources. In this work, we proposed a simple microfluidic system that enables anisotropic bacterial attachment to the drug containing micro chamber made of biodegradable polymer. A pin-ball type trapper can capture only one micro chamber at a fixed configuration. The efficiency of the trapper was analyzed by monitoring the motion of chambers. More than 70% of trapper was filled with the micro chamber within seconds, leading high throughput applications. We are planning to introduce modified Salmonella bacteria for absorbing them to the specific sides of the micro chamber. After releasing the chamber, one would use it as a microrobot by the chemotaxis of the attached bacteria towards the targeted site.