A device that releases chemical compounds in small volumes and at multiple, well defined locations would be a powerful tool for clinical therapeutics and biological research. Many biomedical devices such as neurotransmitter-based prostheses or drug delivery devices require precise release of chemical compounds. Additionally, the ability to control chemical gradients will have applications in basic research such as studies of cell microenvironments, stem cell niches, metaplasia, or chemotaxis. We present such a device with repeatable delivery of chemical compounds at multiple locations on a chip surface. Using electroosmosis to drive flow through microfluidic channels, we pulse minute quantities of a bradykinin solution through four 5-m apertures onto PC12 cells and show stimulation of individual cells using a Ca 2؉ -sensitive fluorescent dye. We also present basic computational results with experimental verification of both fluid ejection and fluid withdrawal by imaging pH changes by using a fluorescent dye. This ''artificial synapse chip'' is a prototype neural interface that introduces a new paradigm for neural stimulation, with eventual application in treating macular degeneration and other neurological disorders. D evices that can repeatedly release chemical compounds in small volumes and at multiple locations would be powerful clinical and laboratory tools. Some clinical therapeutics such as implantable drug-delivery devices (1) and neurotransmitterbased neural prostheses (2, 3) require the controlled release of chemical compounds. However, many of the current devices have limited control or repeatability. In addition, basic research requiring control over chemical gradients, such as studies of cell microenvironments (4-6), stem cell niches (7,8), metaplasia (9), or chemotaxis (10-12), can benefit from a general chemicalrelease device. In these areas of study, the local cellular environment plays a significant role in function; a device that enables control over cellular microenvironments may prove to be a powerful research tool.In this article, we present such a device, with repeatable delivery of chemical compounds at multiple locations on a chip surface. The device consists of an array of four 5-m circular apertures, each connected to a microfluidic channel. Using electroosmosis to drive fluid flow, we show ejection of minute quantities of a bradykinin solution through these apertures onto PC12 cells; with a Ca 2ϩ -sensitive fluorescent dye, we measure stimulation of individual cells. In addition, we use a finite element model to derive basic computational results and provide experimental verification of both fluid ejection and fluid withdrawal through imaging pH changes of a fluorescent dye.We labeled our device an ''artificial synapse chip.'' We built the device for application to a neurotransmitter-based retinal prosthesis, a device that, in essence, mimics a synapse by controlled, repeatable release of neurotransmitters. The use of neurotransmitters for stimulation instead of electric fields provides...
The Artificial Synapse Chip is an evolving design for a flexible retinal interface that aims to improve visual resolution of an electronic retinal prosthesis by addressing cells individually and mimicking the physiological stimulation achieved in synaptic transmission. We describe three novel approaches employed in the development of the Artificial Synapse Chip: (i) micropatterned substrates to direct retinal cell neurite growth to individual stimulation sites; (ii) a prototype retinal interface based on localized neurotransmitter delivery; and (iii) the use of soft materials to fabricate these devices. By patterning the growth of cells to individual stimulation sites, we can improve the selectivity of stimulation and decrease the associated power requirements. Moreover, we have microfabricated a neurotransmitter delivery system based on a 5- micro m aperture in a 500-nm-thick silicon nitride membrane overlying a microfluidic channel. This device can release neurotransmitter volumes as small as 2 pL, demonstrating the possibility of chemical-based prostheses. Finally, we have fabricated and implanted an equivalent device using soft flexible materials that conform to the retinal tissue more effectively. As many of the current retinal prosthesis devices use hard materials and electrical excitation at a lower resolution, our approach may provide more physiologic retinal stimulation.
Micromachining has pushed the limits of photolithography in the vertical direction. We demonstrate a new technique for producing structures in thick photoresists, with excellent contact alignment and high aspect ratios using a standard UV source. In this technique, we exposed the resist from the bottom by defining the mask as part of the substrate. By doing so, we successfully created high aspect ratio and multiple-layer structures. Additionally, the structures have a slight inward taper, a very useful feature for molding. This technique is a new way of thinking about photolithography, allowing novel structures and simplified processing.
The demonstration of localized chemical stimulation of excitable cells illustrates the potential of this technology for retinal prostheses. Although this is only a proof of concept of neurotransmitter stimulation for a retinal prosthesis, it is a significant first step toward mimicking neurotransmitter release during synaptic transmission.
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