Singapore-MIT Alliance for Research & Technology

BioSystems and Micromechanics (BioSyM) Inter-Disciplinary Research Group

BioSyM Highlights
 
Prize winners: Dr.Poon Zhiyong (best presentation), Dr.Smitha & Ms. Aoli (Poster, 1st prize), Dr.Krishna (Poster, 2nd prize) and Dr.Liu Xiaogang (Poster, 3rd prize)
Sections of Poster Session

Emergent heterogeneity in putative mesenchymal stem cell colonies

Bone marrow stromal cells (BMSCs) include a subset of stem cells that are considered promising for developmental studies and therapeutic applications. In this work led by BioSyM PI Prof.Krystyn Van Vliet, it has been observed that BMSC colony formation in real time via time lapsed optical imaging and analysis, to quantify whether and how heterogeneity emerged over multiple cell divisions spanning the duration of a typical colony formation unit assay. These analyses demonstrate that such colonies are neither homogeneous subpopulations of stem cells nor necessarily derived from single originating cells. These direct quantitative observations and visualizations of colony formation provide new insights that are motivated by significant implications for both basic research and stem cell-based therapies.
Colonies observed after four days of growth varied by the number of originating progenies. Of all locations in which colony formation was observed, approximately 35% originated from a single tracked cell, 48% originated from two analyzed cells, and the remainder formed from three or four originating cells that attached near each other at the start of the experiment. Phase contrast images of three representative colonies after four days of growth are displayed, organized by the number of analyzed cells the colonies originated from. Images are montages of nine or sixteen fields of view and were altered post-experiment to artificially color the BMSCs by the progeny they belong to. Cells without color added are BMSCs that migrated into the montaged field of view after initial imaging. Lineage trees of the colonies’ originating cells are also presented, where the width of the lineage lines is representative of the respective cell spread area at each 15 min time point. Lineage trees and images of all colonies at several time points are presented in S1 Fig. Lineage tree outlines indicate the proliferative capacity of the progeny. Dashed line (- -): progeny classified as slow proliferator; dotted line (. . .): progeny classified as moderate proliferator; solid line (–): progeny classified as fast proliferator. Scale bars = 0.5 mm.

 

"Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome", Stem Cell Research & Therapy, 9:268 (2018).

http://news.mit.edu/2018/helping-blood-cells-regenerate-stem-cell-1024

MIT and BioSyM researchers have shown MSCs that were culture expanded on substrata of varying mechanical stiffness were efficient and sustained hematopoietic recovery in vivo.Additionally, results demonstrated that mechanically modulated MSCs can robustly improve the cell secretory profile and improve radiation rescue, as compared to either sorted DhiMSCs subpopulations or unsorted MSCs grown on typical cell culture plastics from the same donor.

In-Vivo hematopoietic recovery

Mesenchymal stem cells (red, with blue nuclei) on a surface with mechanical properties similar to those of bone marrow.

 

Mucoadhesive PLGA Microparticles for Ocular Drug Delivery

BioSyM's findings pave the way for the rational design of mucoadhesive microparticulate ocular drug delivery systems that are capable of enhancing the bioavailability of topically applied drugs to eyes, as well as to other tissues whose epithelial surfaces contain mucosae.

Dawei Ding (SMART), Binu Kundukad (SMART), Ambika Somasundar (NUS), Sindhu Vijayan (SUTD), Saif A.Khan (NUS), Patrick Doyle (MIT/SMART), "Design of Mucoadhesive PLGA Microparticles for Ocular Drug Delivery", ACS Applied Bio Materials, Publication Date (Web): August 16, 2018

Some highlights from BioSyM's recent publications "Mechanical Strain effects on early stages of Oligodendrocyte differentiation", "Role of Monocytes in T-Cell Immunotherapy" and a protocol paper on "Expansion of patient derived CTCs from liquid biopsies".

“Mechanical Strain Alters Cellular and Nuclear Dynamics at Early Stages of Oligodendrocyte Differentiation”, Frontiers in Cellular Neuroscience, Vol. 12, March 2018

Effect of strain on cellular and nuclear dynamics of differentiating Oligodendrocyte Progenitor Cells (OPCs). OPCs induced simultaneously by chemical cues and mechanical strain exhibit significantly lower cell-migration and nuclear-fluctuations (at 24 h post-induction) than cells induced by chemical cues alone.
Charaterizing the role of monocytes in T-Cell Cancer Immunotherapy Using a 3D Microfluidic Model, Frontiers in Immunology, Vol 9, March 2018

(A) A 3D multicellular tumor microenvironment microfluidic model consisting of a middle hydrogel channel (2) flanked by two media channels (1, 3) for the mechanistic study of the effect of monocytes on T cell receptor-redirected T cell (TCR T cell) killing of tumor cell aggregates. Human monocytes were insertedtogether with target HepG2-preS1-GFP cell aggregates in collagen gel in the central hydrogel region (2), while hepatitis B virus (HBV)-specific TCR T cells were added into one fluidic channel (1) to mimic the intrahepatic carcinoma environment. (B) Representative confocal image of a target cell aggregate (in green) surrounded by monocytes (in blue) and HBV-specific TCR T cells (in white), in which the presence of dead target cells is DRAQ7+ (in red). Target cell death is quantified as shown based on the DRAQ7+ volumetric portion in the total volume of each GFP-labeled aggregate.
Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device, Nature Protocols, 13, 34 (2018)

Steps 72–82: Schematic illustration and working principle of CTC cluster formation. (a) Blood samples are obtained by liquid biopsy and lysed to remove RBCs. Nucleated cells are obtained for seeding. (b) Operating principle of CTC cluster formation using specialized tapered microwell structures. In a sample with cluster formation (left), a single cluster forms consistently in each microwell. This occurs through the interaction of patient-derived blood cells (white) with CTCs (green/orange) to promote CTC cluster formation. In negative samples (right), clusters do not form.

 

BioSyM Post-Doc Dr.Khoo Bee Luan is now in the honorable list of 2018’s 10 ‘Innovators Under 35 Asia’

http://emtechasia.com/index.php/innovators-under-35/tr35-honourees

About Khoo Bee Luan

Dr Khoo Bee Luan is a biomedical scientist focused on innovating microfluidic devices for clinical utility. She leads a research team under the Young Investigator grant award by NMRC to utilise a microfluidic device for cancer management and evaluation, termed as the circulating tumour cell (CTC) Cluster Assay. The CTC Cluster Assay aims to mimic parts of the tumour microenvironment in vitro by integrating a confined fluidic niche using microwells with hypoxia and tumour-associated immune cells. She has also developed microfluidic biochips for isolation of primary cancer cells, diseased blood cells or malaria-infected cells with relevance to early disease detection.

Mechanistic action of weak acid drugs on Biofilms (Scientific Reports, 7; 4783 (2017)): BioSyM and SCELSE (NTU) researchers have studied the efficacy of weak organic acid drug on the eradication of biofilms formed by the mucoid strain of Pseudomonas aeruginosa and investigated the commonality of this drug with that of acetic acid. It is shown that the weak acid can penetrate the biofilm matrix and eventually kill 100% of the bacteria embedded in the biofilm.

(A) Schematic of a flow cell. (B) Biofilms are grown in flow cells with a glass base and a PDMS top with a continuous supply of 10% Luria-Bertani broth (LB). The drug is injected into the flow cell through the PDMS Microcolonies grow on the glass base to a size of approximately 200 μm after a period of 2 days.

A 3D microfluidic model for preclinical evaluation of TCR-engineered T Cells against solid tumors:

BioSyM researchers and collaborators from Duke-NUS, A-STAR (IMCB, SICS) demonstrate an easily reproducible
and simple system to test whether TCR-engineered T cells can overcome the physical and metabolic
barriers present in the tumor microenvironment. The system is composed of a microdevice-based cellular
assay in which cancer cells and T cells interact in a 3D space. Conditions can be precisely regulated and the
ability of distinct preparations of engineered T cells to reach and kill cancer cells can be tracked over time.
We demonstrate that this 3D microdevice assay can measure the antitumor efficacy of TCR-engineered T
cells and that it can be easily customized to study the effect of specific biological conditions and clinical
scenarios on their function.

Andrea Pavesi (SMART/A*STAR-IMCB), Anthony T Tan (Duke-NUS), S.Koh (A*STAR-SICS), M.Colombo, E.Antonecchia, Carlo M, Giulia Adriani (SMART), M.T.Raimondi, R.D.Kamm (SMART/MIT), Antonio Bertoletti (Duke-NUS)/A*STAR-SICS), A 3D microfluidic model for preclinical evaluation of TCR-engineered T Cells against solid tumors, JCI Insight, June (2017)

BioSyM researchers at SMART, NUS & MIT have developed a novel interferometer for wide-field imaging using Fourier transform (FT) spectroscopy, which enables many biomedical applications requiring hyperspectral analysis through demonstration on fluorescent beads, cell and tissue specimen.A compressive data acquisition scheme is demonstrated for multiplexed imaging with many fluorescent species. In addition, a wide-field spectral Raman imaging is demonstrated with the new FT interferometer.  (Dushan et al "Near-common-path interferometer for imaging Fourier-transform spectroscopy in wide-field microscopy, Optica, 4 (5), May 2017)

 

Fluorophores with near-infrared (NIR) emissions play a crucial role in numerous bioimaging and biosensing applications. These NIR fluorophores afford highly attractive optical properties, such as deep penetration depths, good signal-to-noise ratios, and minimal tissue damages. BioSyM researchers Dr. Liu Xiaogang and Professor Matthew Lang with their collaborators have rationally developed a new class of near-infrared fluorophores with bright one-photon and two-photon emissions at ~740 nm, large Stokes shifts (~80 nm), significant two-photon action absorption cross-section (~185 GM at 820 nm), excellent water solubility, outstanding photostability and low toxicity. They also demonstrated their biological applications in mitochondrial labelling, deep tissue imaging and H2S detection in live cells and mice. Their paper is now published online in “Chemistry – an European Journal” and has been selected as a “Hot Paper” by the Editor. "Hot Papers are chosen by the Editors for their importance in a rapidly evolving field of high current interest”.

(a) Colocalization images of A375 cells incubated with 1 (1 mm,30 min) and MitroTracker Green (MG, 1 mm, 30 min): (i) emission from channel 1 (MG; lex 488 nm; lem 495–530 nm); (ii) emission from channel 2 (1; lex 635 nm; lem 690–740 nm); (iii) overlay of channels 1 and 2; (iv) intensity scatter plot of channels 1 and 2. (b) Fluorescence images (pseudo color) of a nude mouse, (i) 5 (ii) 10, and (iii) 15 min after injecting 1 into the tail veins of the mouse ([1]=20 mm; vol=20 mL). (c) Two-photon fluorescence imagingof rat liver tissue stained with 1, at the imaging depth of (i) 280, (ii) 320, (iii) 360, and (iv) 400 mm ([1]=10 mm).

 

 

 

BioSyM research published in Lab Chip, 17, 448, (2017):A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood–brain barrier

BioSym researchers (Giulia, Andrea & Roger) along with collaborators from Duke-NUS report a novel 3D neurovascular microfluidic model consisting of primary rat astrocytes and neurons together with human cerebral microvascular endothelial cells. These three cell types in our neurovascular chip (NVC) show distinct cell type-specific morphological characteristics and functional properties. In particular, morphological and functional analysis of neurons enables quantitative assessment of neuronal responses, while human cerebral endothelial cells form monolayers with size-selective permeability similar to existing in vitro blood–brain barrier (BBB) models.
Neurovascular unit. (A) Schematic representation showing blood vessels, astrocytes and neurons within the brain tissue. The inset shows the selectivity of the endothelial monolayer. (B) Scheme of the four channels in the neurovascular chip (NVC) and the location of the three different cell types. From left to right: medium (pink), neurons (orange), astrocytes (blue), and endothelial cells (green). (A) Device with gel channels filled with food dye for visualization purposes (left), schematic layout of the 3D neurovascular chip (NVC) and enlarged view of the channels: two central hydrogel regions for co-culturing astrocytes (blue) and neurons (orange) and two sidechannels for hosting endothelial cells and media (green and red, respectively). (B) Timeline of the experiment. (C) Phase contrast images showing growth of primary neurons, primary astrocytes and endothelial cells (HUVEC and hCMEC/D3), in their respective microfluidic channels.

BioPhysical Society TV 2017 has featured a video on BioSyM released during their recent event "BioPhysical Society 61st Annual Meeting (https://www.biophysics.org/2017meeting/Home/tabid/6672/Default.aspx), held from Feb 11-15, 2017, New Orleans, Louisiana, USA.

BioSyM Alumna Dr.Krishna Agarawal has secured Marie Curie Individual Fellowship. This fellowship carries a research funding over 2 years and she will be applying MUSICAL (Multiple signal classification algorithm) for imaging viruses and bacteria in liver cells. She will carry out her research at University of Tromso, Norway.

 

STRAITS TIMES reports BioSyM Research: "Singapore-made device to aid in developing cancer therapy"

The device between Dr Pavesi's fingertips is no larger than a stamp but he hopes to use it to explore electric fields and cancer cells. Team member Giulia Adriani is holding the mould used to make the tool.ST PHOTO: LAU FOOK KONG

 

Atlas of Science has published our "Layman" summary (titled "Microfluidic tumor models help pre-clinical screening of T cell cancer immunotherapies”) of our recent article published in drug discovery today

Schematic representation of the tumour microenvironment (TME) and its main constituents that represent a challenge for T cell immunotherapy (left). 3D TME microfluidic models used to study cancer metastasis and tumor-immune system interaction mechanisms (center) represent a preclinical screening platform for T cell immunotherapies.

BioSyM researcher awarded Open Fund - Young Individual Research Grant (YIRG)

BioSyM Post-Doctoral researcher Dr.Khoo Bee Luan has been awarded the NMRC’s  Open Fund - Young Individual Research Grant for advancing her research work on “Microfluidic Assay for Routine Evaluation of Anti-Cancer Drug Therapy on Clinical Human Circulating Tumor Cells”.

The outcome of this work will be impactful not only in terms of elucidating the mechanism of cancer metastasis, but also finding many new clinical counter-measures to combat the significant challenge of metastatic cancer in clinics

 

BioSyM & MBI researchers have demonstrated an efficient approach to evaluate response to cancer drug using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment.

"Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment", Science Advances, 2 : e1600274 (2016)

 

SMART-BioSyM advances cancer therapy – Tumour Treating Fields – with a novel microfluidic device

- Tumour Treating Fields (TTFields) are low intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. This non-invasive treatment targets solid tumours and has been FDA-approved for Glioblastoma (brain cancer).


- SMART innovation - 3D microfluidic device with embedded electrodes - enables the application of an electric field therapy to single or aggregated cancer cells in a 3D microenvironment. This not only expedites and lowers the cost of the entire research process, but also renders customised therapy a reality as patient’s own cancer cell can be injected into the microfluidic device and tested.

Details published in Engineering a 3D microfluidic culture platform for tumor-treating field application", Scientific Reports
(Top, L to R): PDMS microfluidic device with embedded electrodes; Lung cancer aggregates in the 3D hydrogel within device, in co-culture with non-cancerous cells; Injecting lung cancer cells into device (Bottom pix): Researchers Andrea and Giulia showing images of stimulated & dispersed non-stimulated cancer aggregates

 

Guided by quantum chemical calculations, BioSyM researchers, Liu Xiaogang (SMART Scholar) and Matthew Lang (PI), in collaboration with scientists from Chinese Academy of Sciences, have demonstrated a simple chemical substittution that greatly enhances fluorophore performance. They also revealed two major mechanisms that compromise the brightness and photostability of fluorophores. Such knowledge is a critical step towards developing high-performance fluorophores for advanced fluorescence imaging. Their results have been published in Journal of the American Chemical Society, one of the most prestigious chemistry journals.

X. Liu*, Q. Qiao, W. Tian, W. Liu, J. Chen, M. J. Lang, Z. Xu*, “Aziridinyl fluorophores demonstrate bright fluorescence and superior photostability through effectively inhibiting twisted intramolecular charge transfer”, Journal of American Chemical Society, 2016, DOI: 10.1021/jacs.6b03924.

BioSyM researchers and collaborators have demonstrated a novel microfluidic device with embedded electrodes that enables the application of an alternating electric field therapy to cancer cells in a 3D extracellular matrix. The metastatic potential of the cancer cells and the proleferation rate were reduced after electric field treatment. These results form the basis for the potential use of both Chemotherapy and ElectricFieldTherapy in frontline cancer treatment regimens. {"Engineering a 3D microfluidic culture platform for tumor-treating field application", Scientific Reports}

Microfluidic device for Electric Field application. (A) Photo of three devices filled with food color dyes. Device cross section (B) and 3D CAD overview (C) with the conductive mixture (Ag/PDMS) in dark grey, cellculture media in pink, and 3D hydrogel region in green.
Equivalent electric circuit model of the microfluidic device

BioSyM and A*STAR researchers have developed new insights into how macrophages of polarized subtypes and carcinoma cells interact in the tumor microenvironment, paving way for understanding possible mechanisms for carcinoma-macrophage signalling in Epithelial-mesenchymal transition (EMT). This work is now published in the Journal "Macrophages"

Schematic representations of carcinoma aggregate dispersion at 0h and 36h in contact and separate condition into the microfluidic device. First column shows the macrophage subtype and the microfluidic device (media channel in pink, media channel with HUVECs in green, 3D collagen matrix for carcinoma aggregate and macrophage interactions). Second and third columns show the schemes for the contact or the separated condition at 0h and 36h (A549 aggregates in red; M0, M1, M2b and M2c in green; M2a in blue)

BioSyM and MBI researchers have evaluated the Single Cell Analysis (SCA) technique to address heterogenity issues associated with cancer cells. The complete review is now published in "International Journal of Cancer"

The illustration covers the process of tumor biopsy from a patient, to downstream characterization using pooled cell analysis or single cell techniques. The bar charts demonstrates the frequency of gene/protein expression detected; pooled sample analysis incorporates several tumor cell subpopulations, which may mask signals or lead to inaccurate display of relative expression levels, while single cell analysis allows breakdown to reveal individual heterogeneity for a more accurate assessment.

Prof. C.T.Lim of NUS, one of the BioSyM PIs, is elected to be inducted into Medical and Biological Engineering Elite by The American Institute for Medical and Biological Engineering (AIMBE)

BioSyM research published in Nature Protocols, Jan 2016 issue: Ultra-fast, label-free isolation of circulating tumor cells from blood using spiral microfluidics, Majid Ebrahimi, et al.,

Overview of CTC isolation using spiral microfluidics. (a) Schematic of CTC enrichment by a spiral channel. CTCs are focused near the inner wall, whereas WBCs, RBCs and platelets are focused closer to the outer wall at the outlet because of the combined effects of inertial lift force and Dean drag force. (b) Left, optical image of single and multiplexed spiral biochips for high-throughput CTC isolation from lysed blood. Right, schematic illustrating the possible downstream techniques for functional characterization of CTCs isolated using a spiral biochip.

Protein folding and DNA condensation are two important instances that a biopolymer undergoes a conformation change from a coiled state to a globular state. Such coil-globule transition often occurs in confined space due to cell membranes.BioSyM researchers have found that confinement makes the transition easier and faster, because the coiled conformation is disfavored in confined space. The details are published in Scientific Reports(Nature Publications)

BioSyM Alumni Dr.Majid Ebrahimi Warkiani has been chosen as one of the 10 Honourees of MIT TR35 Innovators Under 35 Asia. Majid was one of the major contributors to BioSyM's research on Microfluidic Cell sorting and its application to sorting Circulating Tumor Cells (CTCs).

http://www.emtechasia.com/index.php/innovators-under-35/tr35-honourees

 

SMART-BioSyM start-up, AIM Biotech's microfluidics device (shown here) has an array of culturing sections, each with three chambers: a middle chamber for hydrogel and any cell type, and two side channels for culturing additional cell types.

Spinout’s microfluidics device better models how cancer and other cells interact in the body: https://www.aimbiotech.com/

 

BioSyM - A*STAR - NUS researchers develop microfluidic "in vitro" platform to study Tumor Associated Macrophages (TAMs)

Researchers from SMART-BioSyM and A*STAR Institutes SIgN and IMCB have developed a novel microfluidic based in vitro tumor microenvironment. This platform was utilized to study the role of individual subtypes of macrophages (M0, M1, M2a, M2b and M2c) in human lung adenocarcinoma (A549) aggregate dispersion, as a representation of epithelial- mesenchymal transition (EMT). The findings may help in the development of immunotherapies based on enhancing the tumor-suppressive properties of TAMs. The results are now published in Oncotarget.

Microfluidic co-culture platform to study the interactions between carcinoma aggregates and macrophages. A. Photograph of the polydimethyl siloxane (PDMS) device. B. Schematic images of an enlarged, isometric view of the channel layout showing the orientation of co-culturing carcinoma cell aggregates and endothelial cells (HUVECs), with macrophages either physically contacting (left panel; 1: media channel; 2: A549 aggregates and macrophages gel channel; 3. supporting gel channel; 4: HUVEC monolayer) or cultured under separated conditions (right panel; 1: media channel; 2: A549 aggregates gel channel; 3. macrophages gel channel; 4: HUVEC monolayer). C. HUVEC monolayers formed in the microfluidic channel. Green: GFP-HUVECs. D–F. E-cadherin immunocytochemical staining. E-cadherin expression of A549 aggregates at 0 h (D), E-cadherin expression of A549 aggregates in the absence (E) or presence (F) of macrophages at 36 h. Green: E-cadherin staining, red: mCherry A549 nuclei.

 

Membrane-less microfiltration using inertial microfluidics

BioSyM researchers have developed a membrane-less microfiltration system by massively parallelizing inertial microfluidics to achieve a macroscopic volume processing rates (~ 500 mL/min). This platform has the desirable combinations of high throughput, low-cost, and scalability, making it compatible for a myriad of microfiltration applications and industrial purposes. The details are described in Scientific Reports (Nature Publishing) 5, 11018 (2015)

(a) Schematic of a trapezoidal cross-section spiral microchannel illustrating the principle of particle focusing and trapping within the Dean vortices. In the filtration mode, all the suspended particles inside the fluid are trapped and focused near the outer wall where strong vortices exist. In the fractionation mode, smaller particles are trapped inside the Dean vortices and remained near the outer wall while bigger particles are focused near the inner wall, thus allowing particle separation at the outlets. The key to changing from one mode to another relies on the magnitude of the hydrodynamic forces in the microchannels that are in turn relies on particle sizes, flow rates and channel dimensions. (b) Schematic 3D drawing of a highthroughput module consists of four spirals connected together. This design is employed to create the master mold using precision micromilling, and then used in soft lithography to replicate PDMS layers. (c) Optical image of a high-throughput system consists of multiple PDMS layers with embossed microchannels (i.e., 40 multiplexed devices) bonded for continuous cell retention from large sample volumes along with a 3D printed guide layer for fluid delivery. The throughput of this system (a single unit) can be as high as 240 mL/ min or ~350 L/Day. This throughput can be further increased (up to thousand litres per day) through parallelization.

 

Controlled electrical, mechanical and biochemical stimulation of Cells on a chip

BioSyM researchers describe in a new publication in Scientific Reports (Nature Publishing) 5, 11800 (2015), the design and fabrication of a microfluidic device capable of simultaneously providing mechanical, electrical, and biochemical stimulation, and subsequently extracting detailed morphological and gene-expression analysis on the cellular response.

Design of the microfluidic platform developed to investigate the biological cell responses to various stimuli. (A) Schematic view of the device for applying electrical, mechanical and chemical stimulations. The central channel (in red) is the media channel to provide nutrients and soluble factors to cells. The pneumatic channels (in light blue) perform mechanical stimulation by stretching the PDMS membrane (yellow arrows) where the cells are cultured. The electrical layer contains two conductive regions composed of a mixture of CNTs and PDMS (in light gray), which are connected to the stimulator through two external gold-coated connectors (in red and black). The uniform electric field across the cell culture
region is represented by the red arrows. (B) Cross section of the device in the unstimulated configuration. (C) Cross section of the device in the electromechanical stimulated configuration. Applying vacuum in the two lateral pneumatic channels (in light blue) allows stretching of the cells on the deformable membrane (in yellow).

 

Enhancing malaria diagnosis through microfluidic cell enrichment

BiosyM researchers have demonstrated an approach to increase the sensitivity and reliability of malaria diagnosis by Magnetic Resonance Relaxometry (MRR) using a microfluidic cell enrichment technique. The details are published in Scientific Reports, 5: 11425 (2015)

(a) Schematic diagram of the margination device. The microfluidic separation device that has one inlet, two outlets, and a margination channel of 50 μ m in width and 20 mm in length. The insets show the schematic of the cross-sectional view of hRBCs and iRBCs distribution before and after passing through the margination channel. The initially randomly distributed stiffer iRBCs are marginated towards the sidewall, while the more deformable hRBCs migrate towards the axial center of the microchannel. (b) Schematic diagram of the bench top MRR system for R2 measurement. The blood sample is centrifuged in a microcapillary tube and loaded into MRR receiver coil placed inside a 0.5 T permanent magnet. The receiver coil is connected to a bench-top spectrometer for MRR measurements.

 

PREDICTING PATIENT RESPONSE TO CANCER TREATMENTS VIA MONITORING CULTURES OF CIRCULATING TUMOR CELLS

A collaborative study led by scientists from the Mechanobiology Institute (MBI), Singapore MIT Alliance for Research and Technology (SMART) - BioSystems and Micromechanics (BioSyM) and the National University Hospital at the National University of Singapore has led to the development of a novel technique for culturing circulating tumor cells (CTCs). This assay could be used for predicting cancer treatment outcome. Their work is published in Oncotarget on 6 May 2015.

 

BioSyM's research was displayed at Singapore's 1st Tech Carnival on 25th April 2015 @ Suntech City Tower, as part of SMART's research showcase on healthcare, environment and mobility. The video displayed 4 of BioSyM's projects: Miniaturised Magnetic Resonanance Relaxometry for malaria detection, Bio-Imaging, Microfluics Cell sorter and 3D microfluidics for drug screening

 

International Media visits SMART BioSyM labs @ CREATE

Biosym hosted a group of International Media for a lab visit on 20th April 2015. BioSyM researcher Dr.Andrea Pavesi and his collaborator from Duke-NUS Dr.Tan Anthony Tanoto described our 3D microfluidic technology and its clinical applications in cancer treatment. Mr.Kuan Chee Mun, CEO of AIM Biotech described his company's path in commercializing BioSyM's technology.

Malaria detection using inertial microfluidics

BioSyM researchers have developed a label-free, shear-modulated inertial microfluidic system to enrich malaria parasites from blood so as to facilitate a more reliable and specific PCR-based malaria detection. The technique is 100X more sensitive than the gold standard conventional microscopy analysis of thick blood smears. The details are published in the journal Lab On A Chip.

Origin of Metastable Knots in Single Flexible Polymer Chains

Long polymer molecules such as DNA can find themselves in knotted conformations. BioSyM researchers develop a new theory for the size distribution of knots on a flexible polymer such as DNA. Knotted DNA molecules present interesting phenomena in the process of sequencing genomes during nanopore translocation. The work is published now in Physical Review Letters, 114, 037801 (2015)

Cell therapy in pre-clinical models of bone marrow injury

BioSyM researchers demonstrate the Mesenchymal Stem Cell (MSC) subpopulation’s increased efficacy as a systematically administered cell therapy in preclinical models of bone marrow injury. Compared to survivability of 0% using current “state of the art” but functionally heterogeneous MSCs, this MSC subpopulation achieved >85% survivability. This study highlights the opportunity for rapid clinical translation of BioSyM's cell sorting approach and of this MSC subpopulation for several emerging applications of MSC regenerative medicine. The details of this work is now published in Stem Cells Translational Medicine.

World’s first novel method for label-free identification of stem cells that will lead to more consistent and efficacious stem cell therapies

Left Pix: (L-R) Associate Professor Jerry Chan, SMART co-Investigator; Dr Zhiyong Poon, SMART Research Scientist and  Dr Jacky Lee, former SMART Postdoctoral Associate, with the microfluidics cell sorting device that isolates Mesenchymal  Stem Cells (MSCs) for bone and muscle therapeutic applications. This device can reduce the analysis and decision-making  process from 1 - 2 months to less than 3 days. Right Pix: Close-up of the microfluidics cell sorting device.

The research entitled ‘Multivariate biophysical markers predictive of mesenchymal
stromal cell multipotency’ has been published in the prestigious scientific journal
Proceedings of the National Academy of Sciences.

 

A new way to diagnose malaria

SMART-BioSyM team has now come up with a possible alternative. The researchers have devised a way to use magnetic resonance relaxometry (MRR), a close cousin of magnetic resonance imaging (MRI), to detect a parasitic waste product in the blood of infected patients. The paper describing the technique in the Aug. 31 issue of Nature Medicine.

http://newsoffice.mit.edu/2014/new-method-diagnose-malaria-0831

SMART- BioSyM Press Release

http://smart.mit.edu/news-a-events/press-room/article/49-scientists-in-singapore-develop-groundbreaking-technique-for-early-and-rapid-malaria-diagnosis.html

Worldwide News coverage on our Malaria diagnosis technique

http://www.nature.com/news/quick-test-for-malaria-shows-promise-1.15796
http://www.natureasia.com/en/research/highlight/9416
http://www.bangkokpost.com/news/world/429845/new-test-fast-tracks-diagnosis-for-malaria
http://www.straitstimes.com/news/asia/south-east-asia/story/new-test-fast-tracks-diagnosis-malaria-20140901
http://medicalxpress.com/news/2014-08-malaria-magnetic-fields.html
http://www.eurasiareview.com/01092014-new-way-diagnose-malaria/
http://www.bioportfolio.com/news/article/2048657/Micromagnetic-resonance-relaxometry-for-rapid-label-free-malaria-diagnosis.html
http://www.thephuketnews.com/new-test-fast-tracks-diagnosis-for-malaria-48493.php
http://www.newsmobile.in/articles/2014/09/01/new-test-fast-tracks-diagnosis-malaria
http://www.dailynewsen.com/science/magnetic-detection-of-malaria-shows-promise-h2590320.html
http://www.sciencedaily.com/releases/2014/08/140831150339.htm
http://www.ibtimes.com/scientists-invent-inexpensive-quick-accurate-malaria-test-1674922http://www.deutschlandfunk.de/medizin-ein-schnelltest-fuer-malaria.676.de.html?dram:article_id=296226

In Vivo, Label-free Imaging of liver surface using multi-photon microscopy

BioSyM researchers and collaborators from A*STAR-IBN and NUS have developed a label-free, three-dimensional quantitative and sensitive method to visualize various structural features of liver surface in living rat using multi-photon microscopy (MPM). The work is now published in Applied Physics Letters.

(a) Principle of the TPEF / SHG (two-photon excited fluorescence / Second-harmonic generation) (b) Schematic of the experimental setup.

 

Clinical Validation of an Ultra High-Throughput Spiral Microfluidics for the Detection and Enrichment of Viable Circulating Tumor Cells

Multi-organizational collaborative study among researchers from SMART-BioSyM, NUS, MBI (Mechanobiology Institute), NCCS (National Cancer Centre, Singapore), Clearbridge Biomedics, Sequenom Inc. USA, SGH (Singapore General Hospital), NUH (National University Hospital) has clinically vaildated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis (PLoS One, PloS One, 9(7), e994092014. (2014))

 

Congratulations !!

Dr. Jacky Lee, a NUS / BioSyM Graduate Student was awarded the Chua Toh Hua Memorial Gold Medal 2013/2014 for the best PhD thesis in the life sciences.

Jacky Lee carried out his dissertation work @ BioSyM labs under the supervision of Prof.C.T.Lim (NUS), Prof.Jongyoon Han (MIT/SMART) and Prof.Krystyn Van Vliet (MIT/SMART). He is currently with Ministry of Health, Singapore.

Mr. Andy Tay, an undergraduate student under the supervision of BioSyM Research Fellow Dr Majid EW, has won this year’s Students’ Design Gold Award at the Biomedical Engineering Society, Singapore – 8th Scientific Meeting 2014. Andy won the Gold Medal for the Students’ Design Competition with his project carried out in BioSyM on "Microfluidic Device for Malaria Diagnosis for resource-scarce regions".

With the award, Andy will attend the International Federation of Medical and Biological Engineering (IFMBE) Sponsored Asian-Pacific Medical Device Design Competition 2014 during the 9th Asian-Pacific Conference on Medical and Biological Engineering (APCMBE 2014) at National Cheng Kung University, Tainan, Taiwan, from October 9 to 12, 2014, representing Singapore Biomedical Engineering Society with the same project.

NUH - SMART BioSyM Collaboration

A collaboration between NUH and SMART has developed a percentile chart using the labile glycated haemoglobin A1c (a precursor of HbA1c) to HbA1c ratio to help identify factors that may give rise to potentially spurious HbA1c results. Glycated haemoglobin (HbA1c) is the recommended biomarker for monitoring the glucose control of patients with diabetes. However, the measurement of HbA1c can be adversely affected by several confounding factors. The details of the work has been published in the Journal of Clinical Pathology: doi: 10.1136/jclinpath-2014-202346.

 

Prof.Harry Asada addressing the participants of the BioSyM Short Course on "Biomedical Image Processing with MATLAB" (9th June 2014) @ CREATE

 

  • BioSyM's work in the Journal "Analyst" gets the cover page

 

  • A collaborative study by researchers from BioSyM, MIT, KK Women's and Children Hospital, Singapore and Duke-NUS Graduate Medical School, Singapore on "Endometriosis" has uncovered that the loss of migration inhibitor under hypoxic conditions leads to enhanced endometrial stromal cell motility. The details have now been published in the journal "Fertility and Sterility"

Migration and invasion under physiological oxygen tension in endometriosis.

Schematic of decellularized ECM study. MSCs are plated on TCPS and cultured to generate extracellular matrices. The MSCs are decellularized to expose the layer of ECM for proliferation studies with aMSCs.

SPIRAL CHIP: A microfluidic biochip called ClearCell FX can isolate viable circulating tumor cells (CTCs). The blood sample and a saline buffer are pumped into separate inlets. As cells move through the channel, inertial and centrifugal forces ultimately cause the smaller red and white blood cells to flow along the channel’s outer wall and the larger CTCs to flow along the inner wall. The channel splits into two, where most blood cells flow toward a waste chamberand the CTCs flow toward a collection container. © CLEARBRIDGE BIOMEDICS PTE LTD
  • BioSyM researchers presented 3 papers on advanced bio-imaging technologies at the SPIE BiOS| SPIE Photonics West Conference (1-6 Feb 2014, San Francicso).
  1. Vijay Raj Singh (SMART), Dipanjan Bhattacharya (SMART/NUS), Paul Matsudaria (NUS), George Barbastathis (MIT/SMART), Peter T. C. So (MIT/SMART), “Image reconstruction methodologies for structured light based laser sheet microscope for thick tissue imaging”, SPIE BiOS| SPIE Photonics West, 1-6 Feb 2014, San Francicso
  2. Elijah Y. S. Yew (SMART), Peter T. C. So (MIT/SMART), "Improving the optical sectioning capability of temporally focused widefield two-photon microscopy" SPIE BiOS| SPIE Photonics West, 1-6 Feb 2014, San Francicso
  3. Yubo Duan (NUS/SMART), Shakil Rehman (SMART), George Barbastathis (MIT/SMART) and Nanguang Chen (NUS), "Aperture design in focal modulation microscopy to improve
    modulation depth", SPIE BiOS| SPIE Photonics West, 1-6 Feb 2014, San Francicso

  • Using a 3D microfluidic device and time-lapse confocal microscopy, BioSyM researchers show for the first time that Delta-like 4 (Dll4) containing exosomes causes tip cells to lose their filopodia and trigger capillary sprout retraction in collagen matrix. The details are published in Scientific Reports, 4, 4031 (2014). This study has demonstrated that exosomes are more than biomarkers and can be developed as a tool for drug delivery.

Dll4 exosomes reduced cell proliferation when applied in the gradient

  • BioSyM researchers have utilized the proprietary 3D microfludic platform to understand angiogenic event that is driven by prolyl hydroxylase inhibitor (PHi) and sphingosine 1-phosphate (S1P) in the presence of fibroblast. The observations not only demonstrate the collaboration of EC and fibroblasts in inducing capillary sprouting but also suggest that the combination of CPX and S1P enhances angiogenesis and thus might be of therapeutic value for the pharmacological induction of tissue repair and regeneration. The details of this work are now published in the journal "Integrative Biology", 18, pp. 1474-84, 2013; http://www.ncbi.nlm.nih.gov/pubmed/24190477

     

    BioSyM researchers with their collaborators from A*STAR-IMCB and NUS/CSIS have developed a rapid, low-cost prototyping method to create microwells for the formation of 3D Multicellular Cancer Aggregates for Drug Screening applications. The details of this work are now published online in "Advanced Healthcare Materials", Aug, 2013.

Cancer Cell migration path in 2D and 3D conditions

BioSyM IRG has completed its relocation to its new facility in CREATE (Sept/Oct-2012). The state of the art facility now includes wet labs in level 4 of the Enterprise Wing and bio-imaging labs in the basement.