Hyunjoo Jenny Lee

In vivo optical modulation of neural signals using monolithically integrated two-dimensional neural probe arrays

Integration of stimulation modalities (e.g. electrical, optical, and chemical) on a large array of neural probes can enable an investigation of important underlying mechanisms of brain disorders that is not possible through neural recordings alone. Furthermore, it is important to achieve this integration of multiple functionalities in a compact structure to utilize a large number of the mouse models. Here we present a successful optical modulation of in vivo neural signals of a transgenic mouse through our compact 2D MEMS neural array (optrodes). Using a novel fabrication method that embeds a lower cladding layer in a silicon substrate, we achieved a thin silicon 2D optrode array that is capable of delivering light to multiple sites using SU-8 as a waveguide core. Without additional modification to the microelectrodes, the measured impedance of the multiple microelectrodes was below 1 MΩ at 1 kHz. In addition, with a low background noise level (±25u2009μV), neural spikes from different individual neurons were recorded on each microelectrode. Lastly, we successfully used our optrodes to modulate the neural activity of a transgenic mouse through optical stimulation. These results demonstrate the functionality of the 2D optrode array and its potential as a next-generation tool for optogenetic applications.

Multiplexed Detection of Epigenetic Markers Using Quantum Dot (QD)-Encoded Hydrogel Microparticles.

Epigenetic alterations in gene expression are influenced by experiences and environment, resulting in significant variation of epigenetic markers from individual to individual. Therefore, it is imperative to measure various epigenetic markers simultaneously from samples of individual subjects to accurately analyze the epigenetic markers in biological samples. Moreover, the individualized genome-wide analysis has become a critical technology for recent trends in clinical applications such as early diagnosis and personalized medicine screening of numerous diseases. The array-based detection of modified histones, conventionally used for multiplexed analysis of epigenetic changes, requires pooling of samples from many subjects to analyze population-wise differences in the expression of histone markers and does not permit individualized analysis. Here, we report multiplexed detection of genome-wide changes in various histone modifications at a single-residue resolution using quantum dot (QD)-encoded polyethylene glycol diacrylate (PEGDA) hydrogel microparticles. To demonstrate the potential of our methodology, we present the simultaneous detection of (1) acetylation of lysine 9 of histone 3 (Ac-H3K9), (2) dimethylation of H3K9 (2Me-H3K9), and (3) trimethylation of H3K9 (3Me-H3K9) from three distinct regions in the brain [nucleus accumbens (NAc), dorsal striatum (DSt), and cerebellum (Cbl)] of cocaine-exposed mice. Our hydrogel-based epigenetic assay enabled relative quantification of the three histone variants from only 10 μL of each brain lysate (protein content = ∼ 1 μg/μL) per mouse. We verified that the exposure to cocaine induced a significant increase of acetylation while a notable decrease in methylation in NAc.

A new monolithically integrated multi-functional MEMS neural probe for optical stimulation and drug delivery

We present a monolithically integrated multi-functional MEMS neural probe by integrating both an embedded microfluidic channel for drug delivery and a SU-8 optical waveguide for optical stimulation. In this work, we used a controlled glass reflow process to form an embedded glass layer which serves as both the cover for the microfluidic channel and the cladding layer for the optical waveguide. Using this simple fabrication process, we achieved a compact structure integrated with multiple stimulation modalities. Using our multifunctional neural probe, we demonstrated successful in vivo experiments by optically and chemically activating neurons and recording neural spike signals from individual neurons with a high SNR.

MEMS neural probe array for multiple-site optical stimulation with low-loss optical waveguide by using thick glass cladding layer

We present a MEMS neural probe array for multiple-site optical stimulation with low-loss SU-8 optical waveguides. An embedded 20-μm-thick cladding layer was formed by glass reflow process; due to this embedded structure, no additional thickness was required. In addition, optical loss was reduced by using the thick cladding layer and integrating a thick SU-8 layer as a core layer. The low-loss optical waveguide enables multiple-site stimulation with two-step optical splitters. Using the presented probe array, we also demonstrate a successful in-vivo optical stimulation through recording of neural signals from the hippocampus of a transgenic ChR2-YFP mouse. Recorded neural signals were synchronized with light pulses, which confirms that neurons were successfully stimulated by the blue light and the integrated electrode array successfully recorded the neural signals from activated neurons.

Versatile Size and Shape Microlens Arrays With High Numerical Apertures

We present close-packed microlens arrays (MLAs) with high numerical aperture (NA) over a large range of dimensions based on glass blowing process and replication method. Polydimethylsiloxane (PDMS) MLAs with diameters from (50~mu ) m to 1 mm and a high NA of 0.37 (maximum achievable NA for a PDMS plano-convex lens) are demonstrated, which are difficult to achieve with the conventional methods for large microlenses. In addition, MLAs with various fill-factors up to 96.1% and different base shapes are demonstrated. By adjusting the cavity depth and the chamber pressure, the ratio of sag height and diameter can be further adjusted.

MEMS devices for drug delivery

Abstract Novel drug delivery systems based on microtechnology have advanced tremendously, but yet face some technological and societal hurdles to fully achieve their potential. The novel drug delivery systems aim to deliver drugs in a spatiotemporal‐ and dosage‐controlled manner with a goal to address the unmet medical needs from oral delivery and hypodermic injection. The unmet needs include effective delivery of new types of drug candidates that are otherwise insoluble and unstable, targeted delivery to areas protected by barriers (e.g. brain and posterior eye segment), localized delivery of potent drugs, and improved patient compliance. After scrutinizing the design considerations and challenges associated with delivery to areas that cannot be efficiently targeted through standard drug delivery (e.g. brain, posterior eye segment, and gastrointestinal tract), this review provides a summary of recent advances that addressed these challenges and summarizes yet unresolved problems in each target area. The opportunities for innovation in devising the novel drug delivery systems are still high; with integration of advanced microtechnology, advanced fabrication of biomaterials, and biotechnology, the novel drug delivery is poised to be a promising alternative to the oral administration and hypodermic injection for a large spectrum of drug candidates. Graphical abstract Figure. No Caption available.

Micromachined ultrasound transducer array for cell stimulation with high spatial resolution

In this work, we present a piezoelectric micromachined ultrasonic transducer (pMUT) array for local stimulation on cultured cells with a high spatial resolution for the first time. We used a bulk piezoelectric film that has a higher piezoelectric coefficient (d31) than that of the thin film materials to achieve high acoustic power within a small membrane. The 500-μm-wide and 55-μm-thick transducer membrane exhibits a resonant frequency of 780 kHz, which is within the effective frequency range for stimulating cells. We also demonstrate successful in vitro experiments by stimulating cells using the fabricated pMUT array and verifying the stimulation using fluorescence calcium imaging. Using fluorescence imaging, we observed an increase in Ca2+ level of TRPA1 expressing HEK293T cells under ultrasound sonication, which confirms that TRPA1 channel in HEK293T cells was activated by ultrasound.

Effects of Fabrication Process Variation on Impedance of Neural Probe Microelectrodes

Effects of fabrication process variations on impedance of microelectrodes integrated on a neural probe were examined through equivalent circuit modeling and SPICE simulation. Process variation and the corresponding range were estimated based on experimental data. The modeling results illustrate that the process variation induced by metal etching process was the dominant factor in impedance variation. We also demonstrate that the effect of process variation is frequency dependent. Another process variation that was examined in this work was the thickness variation induced by deposition process. The modeling results indicate that the effect of thickness variation on impedance is negligible. This work provides a means to predict the variations in impedance values of microelectrodes on neural probe due to different process variations.