Singapore Institute for Neurotechnology

Singapore, Singapore

Singapore Institute for Neurotechnology

Singapore, Singapore

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Sahni G.,National University of Singapore | Toh Y.-C.,National University of Singapore | Toh Y.-C.,Singapore Institute for Neurotechnology
20th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2016 | Year: 2016

In-vitro human pluripotent stem cells (hPSCs) cultures can provide a reasonable platform for designing disease specific models to study early neural developmental processes and disease, such as neural tube defects (NTDs). The present study reports a novel method to generate spatially patterned hPSC-based 3D neuroepithelium structures achieved by the combination of cell micropatterning and a multi-step induction protocol in hPSC cultures. This represents a potential method to design a scalable human-relevant system for early neural developmental disease modelling.


Sun Y.,National University of Singapore | Thakor N.,Singapore Institute for Neurotechnology
IEEE Transactions on Biomedical Engineering | Year: 2016

Photoplethysmography (PPG) is a noninvasive optical technique for detecting microvascular blood volume changes in tissues. Its ease of use, low cost and convenience make it an attractive area of research in the biomedical and clinical communities. Nevertheless, its single spot monitoring and the need to apply a PPG sensor directly to the skin limit its practicality in situations such as perfusion mapping and healing assessments or when free movement is required. The introduction of fast digital cameras into clinical imaging monitoring and diagnosis systems, the desire to reduce the physical restrictions, and the possible new insights that might come from perfusion imaging and mapping inspired the evolution of the conventional PPG technology to imaging PPG (IPPG). IPPG is a noncontact method that can detect heart-generated pulse waves by means of peripheral blood perfusion measurements. Since its inception, IPPG has attracted significant public interest and provided opportunities to improve personal healthcare. This study presents an overview of the wide range of IPPG systems currently being introduced along with examples of their application in various physiological assessments. We believe that the widespread acceptance of IPPG is happening, and it will dramatically accelerate the promotion of this healthcare model in the near future. © 2015 IEEE.


Ng E.X.,National University of Singapore | Miller M.A.,Massachusetts General Hospital | Jing T.,National University of Singapore | Jing T.,Singapore Alliance for Research and Technology Center | And 2 more authors.
Biosensors and Bioelectronics | Year: 2016

Cellular enzymes interact in a post-translationally regulated fashion to govern individual cell behaviors, yet current platform technologies are limited in their ability to measure multiple enzyme activities simultaneously in single cells. Here, we developed multi-color Förster resonance energy transfer (FRET)-based enzymatic substrates and use them in a microfluidics platform to simultaneously measure multiple specific protease activities from water-in-oil droplets that contain single cells. By integrating the microfluidic platform with a computational analytical method, Proteolytic Activity Matrix Analysis (PrAMA), we are able to infer six different protease activity signals from individual cells in a high throughput manner (~100 cells/experimental run). We characterized protease activity profiles at single cell resolution for several cancer cell lines including breast cancer cell line MDA-MB-231, lung cancer cell line PC-9, and leukemia cell line K-562 using both live-cell and in-situ cell lysis assay formats, with special focus on metalloproteinases important in metastasis. The ability to measure multiple proteases secreted from or expressed in individual cells allows us to characterize cell heterogeneity and has potential applications including systems biology, pharmacology, cancer diagnosis and stem cell biology. © 2016 Elsevier B.V.


Maksimovic M.,University of Helsinki | Aitta-Aho T.,University of Helsinki | Korpi E.R.,University of Helsinki | Korpi E.R.,National University of Singapore | Korpi E.R.,Singapore Institute for Neurotechnology
European Journal of Pharmacology | Year: 2014

Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. Gria1-/- mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood-stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M., Vekovischeva, O.Y., Aitta-Aho, T., Korpi, E.R., 2014. Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. PloS One. 9, e100188). Here, we complement our study by treating these mice chronically with perampanel, a novel non-competitive antagonist of AMPA receptors, for 4 weeks at the dose of 60 mg/kg diet, and found reduced locomotor hyperactivity in the Gria1-/- animals, while not affecting the wild-type littermates. To study the cellular mechanism by which chronic treatments with glutamate-modulating mood-stabilizing drugs alleviate this hyperactivity, we used the immediate early gene c-Fos protein expression as a marker of neuronal activity in the brain. Chronic lithium, valproate and topiramate blunted the c-Fos expression especially in the dorsal hippocampus of the Gria1-/- mice, with all of them reducing the number of c-Fos-positive cells in the CA3 region and valproate and topiramate also in the dentate gyrus (DG). Lamotrigine and perampanel treatments had the same effect in the all CA1, CA3 and DG subfields of the dorsal hippocampus of Gria1-/- mice. The results suggest that abnormal (hippocampal) glutamatergic transmission underlies the hyperactive phenotype of the Gria1-/- mice in a novel environment, and based on the efficacies of the present chronic drug treatments, this mouse model may serve as a predictive tool for studying novel mood-stabilisers. © 2014 Elsevier B.V.


Han D.,Nanyang Technological University | Zheng Y.,Institute of Microelectronics, Singapore | Rajkumar R.,Nanyang Technological University | Dawe G.S.,Nanyang Technological University | And 4 more authors.
IEEE Transactions on Biomedical Circuits and Systems | Year: 2013

Neural prosthetics and personal healthcare have increasing need of high channel density low noise low power neural sensor interfaces. The input referred noise and quantization resolution are two essential factors which prevent conventional neural sensor interfaces from simultaneously achieving a good noise efficiency factor and low power consumption. In this paper, a neural recording architecture with dynamic range folding and current reuse techniques is proposed and dedicated to solving the noise and dynamic range trade-off under low voltage low power operation. Measured results from the silicon prototype show that the proposed design achieves 3.2 μVrms input referred noise and 8.27 effective number of bits at only 0.45 V supply and 0.94 μ W/channel power consumption. © 2014 IEEE.


Hellsten K.S.,University of Helsinki | Linden A.-M.,University of Helsinki | Korpi E.R.,University of Helsinki | Korpi E.R.,National University of Singapore | Korpi E.R.,Singapore Institute for Neurotechnology
Neuroscience | Year: 2015

A GABA-site agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) at 3mg/kg induces strong anxiolytic response in a transgenic Thy1α6 mouse line ectopically expressing the GABAA receptor α6 subunit gene under the Thy-1.2 promoter. Now, we compared brain activation patterns between Thy1α6 and wild-type mice to identify brain structures potentially mediating this anxiolytic response. Acutely efficient anxiolytics such as benzodiazepines typically depress most brain regions while activating specifically neurons within the central extended amygdala. Gaboxadol treatment (3mg/kg, i.p., 2h) induced a significant increase in c-Fos expression selectively in many Thy1α6 brain regions including the limbic cortex, anterior olfactory nucleus, septal area and central and basolateral nuclei of amygdala. It failed to activate the lateral part of mediodorsal thalamic nucleus (MDL) in the Thy1α6 mice that was activated in the wild-type mice. Detailed mapping of the α6 subunit mRNA by in situ hybridization revealed expression in the middle layers of the isocortex, olfactory areas, hippocampal formation and basolateral nucleus of amygdala (BLA) in the Thy1α6 forebrain. The ligand autoradiographies (t-butylbicyclophosphoro[35S]thionate ([35S]TBPS) and [3H]Ro 15-4513) revealed high levels of pharmacologically active extrasynaptic α6β and α6βγ2 GABAA receptors in these same areas. However, c-Fos induction by gaboxadol treatment in Thy1α6 brain was not restricted to areas highly expressing the α6-containing GABAA receptors suggesting that indirect pathways lead to the paradoxically widespread activation. Interestingly, the activation pattern by gaboxadol at the dose that is anxiolytic in Thy1α6 mice resembled closely that observed after various fear- and stress-provoking challenges. However, our results are consistent with a recent observation that optogenetic activation of specific neuronal pathways in the extended amygdala mediates anxiolytic responses. Our results suggest that the widespread neuronal inhibition as typically associated with benzodiazepines is not the exclusive mechanism of anxiolysis. © 2015 IBRO.


Maksimovic M.,University of Helsinki | Vekovischeva O.Y.,University of Helsinki | Aitta-aho T.,University of Helsinki | Korpi E.R.,University of Helsinki | And 2 more authors.
PLoS ONE | Year: 2014

Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1-/- mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1-/- mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the Gria1-/- mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of Gria1-/- mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of Gria1-/- mice to the level shown by the wild-type Gria1+/+ mice. Gria1-/- mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the Gria1-/- mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the Gria1-/- mouse line can be utilized in screening for new therapeutics. © 2014 Maksimovic et al.


PubMed | National University of Singapore and Singapore Institute for Neurotechnology
Type: | Journal: Biosensors & bioelectronics | Year: 2015

The nematode Caenorhabditis elegans has become an essential model organism in neuroscience research because of its stereotyped anatomy, relevance to human biology, and capacity for genetic manipulation. To solve the intrinsic challenges associated with performing manual operations on C. elegans, many automated chip designs based on immobilization-imaging-release approaches have been proposed. These designs are prone to limitations such as the exertion of physical stress on the worms and limited throughput. In this work, a continuous-flow, high-throughput, automated C. elegans analyzer based on droplet encapsulation and real-time image processing was developed to analyze fluorescence expression in worms. To demonstrate its capabilities, two strains of C. elegans nematodes with different levels of expression of green fluorescent protein (GFP) were first mixed in a buffer solution. The worms were encapsulated in water-in-oil droplets to restrict random locomotion. The droplets were closely packed in a two-layer polydimethylsiloxane (PDMS) platform and were flowed through a narrow straight channel, in which a region of interest (ROI) was defined and continuously recorded by a frame acquisition device. Based on the number of pixels counted in the selected color range, our custom software analyzed GFP expression to differentiate between two strains with nearly 100% accuracy and a throughput of 0.5 seconds/worm.


PubMed | National University of Singapore and Singapore Institute for Neurotechnology
Type: Journal Article | Journal: Muscle & nerve | Year: 2016

A long-term peripheral neural interface is an area of intense research. The use of electrode interfaces is limited by the biological response to the electrode material.We created an electrode construct to harbor the rat sciatic nerve with interposition of autogenous adipose tissue between the nerve and the electrode. The construct was implanted for 10 weeks.Immunohistochemistry showed a unique laminar pattern of axonal growth layered between fibro-collagenous tissue, forming a physical interface with the tungsten micro-electrode. Action potentials transmitted across the intrerface showed mean conduction velocities varying between 6.992.46 and 20.144 m/s.We have demonstrated the feasibility of a novel peripheral nerve interface through modulation of normal biologic phenomena. It has potential applications as a chronic implantable neural interface.


PubMed | Nanyang Technological University, National University of Singapore and Singapore Institute for Neurotechnology
Type: Journal Article | Journal: Advanced healthcare materials | Year: 2016

Bacterial cellulose (BC) is a biocompatible material with high purity and robust mechanical strength used to fabricate desirable scaffolds for 3D cell culture and wound healing. However, the chemical resistance of BC and its insolubility in the majority of solutions make it difficult to manipulate using standard chemical methods. In this study, a microfluidic process is developed to produce hollow BC microspheres with desirable internal structures and morphology. Microfluidics is used to generate a core-shell structured microparticle with an alginate core and agarose shell as a template to encapsulate Gluconacetobacter xylinus for long-term static culture. G. xylinus then secretes BC, which becomes entangled within the shell of the structured hydrogel microparticles and forms BC microspheres. The removal of the hydrogel template via thermal-chemical treatments yields robust BC microspheres exhibiting a hollow morphology. These hollow microspheres spontaneously assemble as functional units to form a novel injectable scaffold. In vitro, a highly porous scaffold is created to enable effective 3D cell culture with a high cell proliferation rate and better depth distribution. In vivo, this injectable scaffold facilitates tissue regeneration, resulting in rapid wound-healing in a Sprague Dawley rat skin model.

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