(459a) Microfabrication of Functional Gels and Application to Controlled Drug Release Microchip

Recently, stimuli-responsive polymer gels attract attention as functional soft materials in the research fields of microfluidic systems. Several applications as a smart microvalve or micropump to switch the direction of flow automatically or extrude fluid are attempted. Conventional microvalves made of hard and dry materials such as piezoelectric elements, shape-memory alloy, etc. are driven by electricity or heat generated from electric energy. In contrast, microvalve made of stimuli-responsive gel can respond to several stimuli other than electricity. And also, there are several advantages such as no heat release, high dust-proof, low power consumption, etc. Consequently, utilization of smart gels will contribute to simplification and miniaturization of device. For microfabrication or micropatterning of gels, lithography method using a mask has been typically employed. In the case of photolithography, additional process to make a photomask is needed and it is often time-consuming.

Here we show simple and convenient method to prepare micropatterned gels by use of a microscope without large-scale or special-order experimental setup. UV light focused by an objective lens was locally irradiated to pre-gel solution in microchannel. By moving the sample stage, microgel with any shape can be prepared at any position in the microchannel. This method would be useful for preparing microgel at target position in microchip as a microvalve or micropump. In this study, controlled drug release microchip has been actually fabricated by utilizing this local photo-irradiation method and pulsatile drug release in response to temperature changes were demonstrated.

For microfabrication of gels, we employed two gelation methods; (1) photocrosslinking of polymers and (2) photopolymerization using a photo-initiator. In order to prepare microgel by photocrosslinking, poly(N-isopropylacrylamide) (PNIPAAm) with photo-reactive azidophenyl groups was synthesized. By irradiating UV spotlight locally to the polymer solution and sweeping the spotlight with moving the sample stage, several shapes of micrometer-sized gels can be easily prepared.

By locally irradiating UV spotlight without sweeping, array of microgels can be also prepared easily. In addition to photocrosslinking method, we tried to prepare thermosentitive microgel array by photopolymerization using a photo-initiator. The photopolymerization method is easier than the photocrosslinknig method mentioned above because the synthetic process of photo-reactive polymer can be eliminated. From the standpoint of formability of prepared gel, the photopolymerization has disadvantages compared with the photocrosslinking because growing radicals easily diffuse out from the UV irradiation area in solution during polymerization. Although there is such a disadvantage, microfabrication of gels by photopolymerization is available from its simplicity.

As one of applications to micro-device by using these maskless local photo-irradiation methods, controlled drug release microchip was fabricated. The microchip is composed of three layers of PDMS with diaphragm structure. The top layer has water-flow channel and the space for fixing the microgel. The middle layer has diaphragm to open and close drug reservoir by swelling and deswelling of the gel. By employing the diaphragm structure, we can avoid a direct contact of the microgel with the drug solution. The bottom layer has the drug reservoir and drug-flow channel. Thermosensitive microgel was prepared in the microchannel by local UV irradiation. At 20°C, the gel swelled to push the diaphragm and close the drug reservoir. When temperature increased to 50°C, the gel deswelled to open the drug reservoir and the model drug was completely released while microgel deswelled. This type of microchip would be applicable as an intelligent and disposable drug delivery patch to release antipyretic only when body temperature increases.

In addition to stimuli-responsive drug release, we have also designed the oscillatory drug release microchip by using self-oscillating gel. By coupling pH-sensitive microgel with pH-oscillating chemical reaction, periodical swelling-deswelling oscillation of the gel was achieved under constant input. If drug reservoir was designed appropriately, such a self-oscillating microgel would act as a microvalve that periodically opens drug reservoir by itself. This system using self-oscillating microgel valve can be applied to new type of controlled drug delivery devices that exhibits pulsatile drug release with preprogrammed periods without external stimuli.

For microfabrication of gels, these local photo-irradiation methods utilizing a microscope we presented here would be useful as an easy and simple method which does not need another process for making photomask or special-order experimental setup. In particular, this maskless method will be effective for preparing microgel in microchannel because troublesome processes for alignment of photomask to the channel are not needed. Since any shape of gel can be also created by this method, application as a new manufacturing method for soft microactuator, microgel valve, etc. is expected.