Impedance-based Biosensors

An optical image and an impedance color-map image of trapped cells on impedance sensing array.

The aim of the project is to develop a hybrid system by integrating a complementary metal-oxide-semiconductor (CMOS) electrical sensor chip and a microfluidic component to enable a large number of cell analysis with single cell resolution. The CMOS sensor chip includes embedded circuit as well as thousands of electrodes array. With integrated microfluidics chamber assembled, thousands of cells can be loaded into the chamber and electrode array using the Dielectrophoretic (DEP) force. Electrical impedance spectroscopy measurement can be done on each sensor electrode and thus the single cell analysis can be realized at fast speed taking advantage of the embedded circuitry design. Qualification of the sensor array was done by comparing with the microscopic results of the thousands of MCF7 cells analysis and the mapping accuracy > 95% was achieved in less than 1 minute.

[Publication] High-density impedance-sensing array on complementary metal-oxide-semiconductor circuitry assisted by negative dielectrophoresis for single-cell-resolution measurement.
[Publication] Microfluidic packaging of high-density CMOS electrode array for lab-on-a-chip applications
[Publication] High Density CMOS Electrode Array for High-throughput and Automated Cell Counting
[Publication] CMOS High Density Electrical Impedance Biosensor Array for Tumor Cell Detection

Conceptual schematics of one unit of vertical through-holes for high-throughput Coulter counter.

The aim of the project is to develop a point-of-care (POC) device to realize high throughput cell counting. IME has developed a silicon chip with a vertical through-hole array which can enable a large number of cells passing through the device with high speed and high throughput. The electrical signal of each channel is recorded when the cells passing through the vertical through-holes and based on the Coulter principle, the cells number and concentration can be analyzed. At the same time, the cell size can be measured as the electrical signal is proportional to the cell volume. Preliminary results of the prototype potential based vertical through-hole coulter counter have shown the high throughput cell counting capability (2000 cells/sec for each channel) and the qualification of the device is done by comparing the results of the prototype and the results from the FACS machine.

[Publication] CMOS-Compatible Silicon-Nanowire-Based Coulter Counter for Cell Enumeration
[Publication] Portable Coulter Counter with Vertical Through-holes for High-throughput Applications

Array of electrochemical sensors for protein/DNA detection.
Detection of molecular profile i.e. DNA, RNA and proteins are essential for diagnosis and prognosis of many diseases. Standard methods for detection of these molecules require lab-based facilities with trained personnel, causing lengthy and costly operating procedures. The delay in diagnosis may cause the disease to develop to its severe forms and reduce the effectiveness of the treatments. Rapid and reliable methods for molecular detection are desired for efficient diagnosis.

IME has developed electrochemical biosensors mainly aiming at point-of-care, using gold sensor electrodes and unique surface modification methods, for rapid and high sensitivity detection of protein and DNA. Using IME’s sensors, we have demonstrated a limit of detection (LOD) of proteins and DNA at 1 pg/mL and 250 fM, respectively. While typical time for standard lab-based detection of protein and DNA are estimated at 1-6 hour, the high sensitivity signal detection with IME’s sensors can be achieved within 10-20 min, which is 4- 24 times shorter than that of the standard methods.

[Publication] Microfluidic electrochemical multiplex detection of bladder cancer DNA markers
[Publication] On-chip electrochemical immunoassay platform for specific protein biomarker estimation in undiluted serum using off-surface membrane matrix
[Publication] Miniaturized Electrophoresis Electrochemical Protein Sensor (MEEPS) for multiplexed protein detections
[Publication] Off surface matrix based on-chip electrochemical biosensor platform for protein biomarker detection in undiluted serum
[Publication] EIS-based biosensor for ultra-sensitive detection of TNF-α from non-diluted human serum
 Microfluidic Devices

IME’s microfluidic chip. On-chip fNRBC identification and single-cell retrieval.
Current prenatal diagnosis to determine aneuploidies is performed by invasive approaches e.g. amniocenteses and chorionic villus sample which impose high risk of fetal loss in 1-5% of cases. Newly developed non-invasive prenatal test (NIPT) with cell-free fetal DNA (cffDNA) utilizes fragmented DNA which is not able to provide definitive diagnosis of the fetus and is prone to false positive diagnosis of up to 50%. Therefore, it is required to develop a true non-invasive prenatal diagnostic technology.

To obtain high accuracy data with less invasive method, IME has developed a non-invasive prenatal diagnosis (NIPD) technology that uses fetal cells from maternal blood for diagnosis. Using IME’s unique design of microfluidic chip, fetal cell can be isolated from maternal blood. We have demonstrated using IME’s microfluidic chips and semi-automated fluid dispensing device that the fetal cell can be identified at 8.7 and 0.21 cells/mL from maternal blood of post terminal of pregnancy (TOP) and on-going pregnancy. Among all 42 clinical samples tested, 1 case of trisomy was identified.

[Publication] Size based sorting and patterning of microbeads by evaporation driven flow in a 3D micro-traps array
[Publication] Microfluidic platform for negative enrichment of circulating tumor cells
[Publication] Microfluidic immunomagnetic cell separation from whole blood
[Publication] An integrated on-chip platform for negative enrichment of tumour cells

Silicon (Si)-based micro-physiological in vitro model of human adipose.
IME is developing a 3D cell culture perfusion system for multi-cell type co-culture (Organ-on-a-chip). Tissue–tissue interactions in the human body play a significant role in determining the success of new pharmaceuticals. The development and use of multi-organ in vitro systems present an opportunity to improve the drug development process. Microfabrication is superior technology that enables high throughput production of microfluidic devices with feature size that is comparable to cell size and enable acceptable cell culture environment with in vivo-like cell-cell interfacing. Our technology would enable growing different type of cells in various architectures which can take the shape with improved cell-cell/tissue-tissue interaction, therefore, enabling the construction of various biological models. We are currently working on three in vitro systems, namely, human skin barrier, intestinal barrier and diabetic adipose tissue.

[Publication] Optimization of micro-fabricated porous membranes for intestinal epithelial cell culture and in vitro modelling of the human intestinal barrier
[Publication] Human adipocyte differentiation and characterization in a perfusion-based cell culture device.
[Publication] On-chip cell activation and simultaneous cytokine detection using in situ magnetic immune assay
[Publication] In vitro micro-physiological immune-competent model of human skin
[Publication] Characterization of tight junction disruption and immune response modulation in a miniaturized Caco-2/U937 coculture-based in vitro model of the human intestinal barrier
 Implantable / Minimally Invasive Medical Devices

(Top) ICP catheter (Bottom) Renal denervation catheter.
IME has developed various type of minimally invasive medical devices packaged via flexible electronics for cardiology and neurology applications, such as vascular graft sensor for early prosthetic graft failure detection, sensor-enhanced guidewire to aid surgeons in endovascular procedures of peripheral artery disease, renal denervation guidewire to address resistant hypertension and other abnormally highly activated sympathetic disease, high density 3D neural probe array microsystem for deep brain neural recording/stimulation application, wireless intracranial pressure (ICP) microsystem for multimodality (temperature, oxygen, and pressure) neuromonitoring of severe head injury patients. These devices are realized using MEMS fabrication process for the sensors and integration with ASIC via Chip-to-Flex packaging techniques.

[Feature] Slimmed down for a better fit, A*STAR Research 
[Feature] Thinner probe array that uses silicon-based microstructure could underpin safer neural implants, Science Daily
 Wearable / Flexible Medical Devices

(Top) Disposable smart sensor patch (Bottom) Dry EEG electrode cap system.
IME has developed various types of wearable devices for healthcare monitoring purposes, such as smart sensor patch for early detection of extravasations, dry electroencephalogram (EEG) electrodes cap for long-term epilepsy monitoring, and a cricoid pressure sensing patch for gastric aspiration procedure. These technologies can monitor a patient’s vital signs or symptoms and provide quantitative feedback, transmit data wirelessly to health providers on abnormal patterns in patient’s condition, allowing for early medical intervention and better patient care.

[Feature] Catching those nasty, leaky drips
[News] IME invents induction films that prevents extravasation