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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-mu m sized microstructures were similar to those of a 1 mu M 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.

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.

Droplet-based microfluidics is receiving much attention in biomedical research area due to its advantage in uniform size droplet generation. Our previous results have reported that droplet size plays an important role in drug delivery actuated by flagellated bacteria. Recently, many research groups have been reported the size-dependent separation of emulsion droplets by a microfluidic system. In this paper, an integrated microfluidic system is proposed to produce and sort specific-sized droplets sequentially. Operation of the system relies on two microfluidic transport processes: initial generation of droplets by hydrodynamic focusing and subsequent separation of droplets by a T-junction channel. The microfluidic system is fabricated by the SU-8 rapid prototyping method and poly-di-methyl-siloxane (PDMS) replica molding. A biodegradable polymer, poly-capro-lactone (PCL), is used for the droplet material. Using the proposed integrated microfluidic system, specific-sized droplets which can be delivered by flagellated bacteria are successfully generated and obtained.

The current stimulation method is preferred over the voltage stimulation method in the visual prostheses based on functional electrical stimulation (FES) due to its accurate charge control property. Previous current stimulators are generally implemented using a static high supply voltage, because current stimulations require high output voltage compliance. This high static supply voltage, however, may harm the tissues or damage the electrodes. This paper proposes a novel integrated circuit (IC) current stimulator with adaptive supply regulator (ASR). In the proposed circuit, the internal power supply voltage is not static, but adaptively regulated to the minimum required voltage for stimulation. The current feedback loop in the ASR adaptively increases the internal supply voltage when the monitored current is smaller than the desired current, and reduces the internal supply voltage when the monitored current is higher than the desired current. With this method, the internal supply voltage of the stimulator is minimized, and potential damages of the tissues due to high voltage (HV) stimulation can be reduced. Also the current feedback loop in ASR enhances the accuracy of the output current and the robustness to the load impedance. The stimulator IC is fabricated using 0.35 micro m bipolar-CMOS-DMOS (BCDMOS) process, and the size of the chip is 2000 micro m by 1500 micro m.

A retinal stimulator is an implantable device restoring vision by supplying a controlled, stimulating electrical signal to people blinded by retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). The resolution requirements of artificial retina systems become increasingly significant in their design as well as their usefulness. At least 32 x 32 pixels are required to provide a minimal visual function. However, a retinal stimulator with a high resolution imposes severe constraints on interface electronics. In this paper, a new stimulator IC (integrated chip) using a channel sharing technique is developed to minimize the circuit size, power consumption, as well as overheating of retina tissues. The proposed current-mode stimulator is fabricated by a 0.35 microm 2-poly/4-metal BCDMOS technology. Attention is given to minimizing the silicon area so that higher channel numbers can be implemented. The stimulator for each channel can provide output current in the range of 0-350 muA. The effective chip area excluding the pads is 1.2 mm x 1.2 mm.

We describe a neural stimulator front-end with arbitrary stimulation waveform generator and adaptive supply regulator (ASR) for visual prosthesis. Each pixel circuit generates arbitrary current waveform with 5 bit programmable amplitude. The ASR provides the internal supply voltage regulated to the minimum required voltage for stimulation. The prototype is implemented in 0.35 μm CMOS with HV option and occupies 2.94 mm₂ including I/Os.

The concepts of microrobots has been drawn significant attentions recently since its unprecedented applicability in nanotechnology and biomedical field. Bacteria attached microparticles presented in this work are one of pioneering microrobot technology for self-propulsion or producing kinetic energy from ambient for their motions. Microfluidic device, especially utilizing laminar flow characteristics, were employed for anisotropic attachment of Salmonella typhimurium flagellated chemotactic bacteria to 30 um × 30 um and 50 um × 50 um microparticles that made of biodegradable polymer. Any toxic chemicals or harmful treatments were excluded during the attachment process and it finished within 100 s for the anisotropic attachment. The attachments were directly confirmed by fluorescent intensity changes and SEM visualization. Chemotaxis motions were tracked using aspartate and the maximum velocity of the bacteria-attached microrobot was measured to be ~5 um/s which is comparable to prior state of art technologies. This reusable and scalable method could play a key role in chemotaxis delivery of functional microparticles such as drug delivery system.

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.

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

This paper presents a method of fabricating pulverized drug, Lapatinib (Tykerb®), loaded micro chambers made of a biodegradable polymer, poly (e-caprolactone) (PCL), for bacteria-based microrobots. The PCL is a biodegradable, biocompatible polymer which is approved by the U.S. Food and Drug Administration (FDA) for use in the implantable medical devices. Lapatinib is approved by the U.S. FDA for the treatment of advanced or metastatic breast cancer. In order to realize bacteria-based microrobots, selective bacterial adhesion is necessary which can enhance directional locomotion of the bacteria-based microrobots. The x-ray lithography process can be used for biodegradable polymer micromachining to fabricate structures with various shapes which can be applied for bacteria-based microrobots. A pulverized drug is used because a liquefied drug cannot be used for the x-ray lithography process. To fabricate pulverized Lapatinib loaded micro chambers, the PCL films are prepared by the solvent casting method and lamination process. Lapatinib is encapsulated between the PCL films by the screen printing method. The x-ray lithography process is then used for fabrication of micro chambers. The fabrication results indicate that the proposed method is appropriate for fabrication of biodegradable polymeric micro chambers encapsulated with the pulverized drug for bacteria-based 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.

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.

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.

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.

Recently, a bacteria-based drug delivery system has been proposed to achieve effective and localized drug delivery. Researchers have shown that flagellated bacteria have a chemotactic property to tumor cells, and they can be used as an energy source for active drug delivery. Our previous results have reported that a circular droplet made by a biodegradable polymer can be used in this bacteria-based, robotic drug delivery. In this paper, using laminated cubic structures made of several layers of biodegradable polymers for bacteria-based microrobot is proposed. The structures are made by laminating polymer layers and then, micromachining them using a deep X-ray synchrotron radiation into 40 μm x 40 μm x 40 μm cubes. The cubic structure is more beneficial in attaching bacteria in only selective surface directions than a circular structure, and in controlling the volume of drugs to be encapsulated with the outer polymer layer.

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.

This paper presents a biodegradable polymer droplet for efficient drug delivery using flagellated bacteria. The biodegradability and the localized delivery are the most important features for determining the efficiency of drug delivery. The proposed droplet is made of poly (DL-lactic-co-glycolic acid) for the biodegradability. It is fabricated using a microfluidic device which has a Y-junction microchannel. The fabricated biodegradable droplet has diameter in the range between 20 µm and 30 µm. Then flagellated bacteria, Serratia marcescens, are attached to these droplets for a localized drug delivery. The Serratia marcescens has a chemotaxis to tumor cells, and thus can be used as an actuation source of self-seeking to the tumor site. This paper presents the proposed concept, droplet fabrication, bacteria attachment, and observed rotational motion of the drug delivery methodology. The experimentally achieved maximum angular velocity is 0.11 rad/sec.

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.