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RESEARCH PROJECTS
• Organ on a Chip and Platform Technology
	» Liver on a Chip: Engineering Liver Sinusoid Functional Unit » Microfabricated Platforms for 3D Epithelial Culture: Matrigel Micropatterns for 3D Morphogenesis » Microfluidic Platform for Studying the Effect of Sickle Cell on Vascular Occlusion
• Electrokinetic Manipulations in Microchannels for Sensing Applications
	» Manipulation of Micro-, Nano-, and Bioparticles Using AC Electrokinetics » Enhancing Binding Kinetics Using AC Electroosmotic Mixing » Microchip Capillary Electrophoresis for Single Cell Proteomics
• Medical Implants and Neural Probes
	» Implantable Microdevice for the Treatment of Hydrocephalus » Flexible Neural Probes for Single Neuron Network and Epidural Stimulation
• Microfabrication Technology Development
	» Excimer Laser Micromachining of MEMS Materials » Inkjet Printing of Conductive Materials and Pattern Transfer » Micro-Fludics Lab (MFL) Modules and Kit for Undergraduate Education » Integration Technologies
“If we knew what it was we were doing, it would not be called research, would it”? -Albert Einstein
PROJECT ABSTRACTS
Organ on a Chip and Platform Technology
Liver on a Chip: Engineering Liver Sinusoid Functional Unit (Sponsored by NSF and NIH) Fundamental liver biology studies predominantly rely on cell culture models. While much progress has been made during the past two decades in prolonging hepatocyte viability and maintaining liver functions in vitro, there are still no authentic liver models that accurately represent the architecture and functions of human liver tissue, thereby limiting advances in liver biology studies and drug development. A new approach to generate an authentic human liver model is proposed in this project. The liver lobule is composed of operational units termed the liver sinusoid, where most of the liver activities take place. The goal of this research is to generate an innovative human liver model (bioreactor) that closely mimics the liver sinusoid functional unit. Microfabrication and microfluidics technologies are combined with cell culture technology to create such an authentic human liver model. The mini-liver on a chip systems will be used to study basic liver biology and pathological processes (e.g. viral infection, alcohol effect) as well as drug delivery/screening research. (Collaborator: Prof. Michael Bouchard of Biochemistry and Microbiology department) T. Sodunke, M. Bouchard, and H. Noh, “Microfluidic Study for Hepatitus B Viral Replication Study,” Biomedical Microdevices, Vol. 10, No. 3, 393-402, 2008. Y-B. Kang, S. Rawat, J. Cirillo, M. Bouchard, and H. Noh, Layered Long-term Co-culture of Hepatocytes and Endothelial Cells on a Transwell Membrane: Toward Engineering the Liver Sinusoid, Journal of Biofabrication, DOI: 10.1088/1758-5082/5/4/045008. 2013 Y-B Kang, T. Sodunke, J. Lamontagne, J. Cirillo, C. Rajiv, M. Bouchard, and H. Noh, Liver sinusoid on a chip: long-term layered co-culture of primary rat hepatocytes and endothelial cells in microfluidic platforms to mimic the liver sinusoid, Biotechnology and Bioengineering, September 2015, DOI: 10.1002/bit.25659
Microfabricated Platform for 3-D Epithelial Culture: Matrigel Micropatterns for 3D Morphogenesis Most human cancers arise from epithelial cells and tissues. In order to understand the mechanisms of tumor initiation and progression, it is crucial to investigate how the genotypic and molecular abnormalities associated with epithelial cancers actually derive the phenotypic changes that are observed in tumors in vivo. Three dimensional (3D) epithelial culture systems, which allow epithelial cells to recapitulate several aspects of glandular epithelial architecture in vivo, may serve as optimal in vitro model for biochemical and cell biological studies involving tumor initiation, progression, and metastasis. In this project we develop microfabricated/microfluidic platforms for 3D epithelial culture that will allow a wide range of applications for high throughput cell-based screening of chemicals, and gene targeting assays. The platform has an array of 3D micropatterns of Matrigel^TM (most widely used extracellular matrix for 3D epithelial culture) on a substrate and single mammary epithelial cells are cultured in the patterned Matrigel to form 3D normal acini (polarized, growth-arrested, hollow acini-like sphere) with continuous perfusion of media. (Collaborator: Prof. Mauricio Reginato of Biochemistry and Microbiology department). T. Sodunke, K. Turner, S. Caldwell, K. McBride, M. Reginato, and H. Noh, “Micropatterns of Matrigel for Three-Dimensional Epithelial Cultures.” Biomaterials, Vol 28/27, 4006-4016, 2007.
Electrokinetic Manipulations in Microchannels for Sensing Applications
Manipulation of Micro-, Nano-, and Bioparticles Using AC Electrokinetics There is a growing need for a technique to manipulate micro-, nano-, and bioparticles in microfluidic environments as lab-on-a-chip research advances. Among currently available techniques, AC electrokinetic techniques that include dielectrophoresis (DEP), AC electroosmosis (AC-EO), and electrothermal effect (ETE) are best suited for the microfluidic applications because the techniques require microelectrodes that can be readily integrated within microchannels and because diverse manipulation of fluids and suspended particles can be achieved simply by changing the frequency of the applied voltage. The goal of this research to achieve a comprehensive understanding and accurate prediction of particle motion in a non-uniform AC field which is at present unavailable, and to develop a combination of DEP, AC-EO, and ETE into a versatile and convenient particle-manipulation technique for micro-, nano-, and biotechnology applications. J. Oh, R. Hart, J. Capurro, and H. Noh, “Comprehensive analysis of particle motion under non-uniform AC electric fields in a microchannel.” Lab Chip, 9, 62-78, 2009. (ISSN: 1473-0189) R. Hart, J. Oh, J. Capurro, and H. Noh, AC Electrokinetic Phenomena Generated by Microelectrode Structures, Journal of Visualized Experiments, http://www.jove.com/index/Details.stp?ID=813, 2008 (Video Journal) (ISSN 1940-087X) D. Lee, C. Yu, E. Papazoglou, B. Farouk, and H. Noh, Dielectrophoretic Particle-Particle Interaction under AC Electrohydrodynamic Flow Conditions, Electrophoresis, 32, 2298–2306, 2011 (ISSN: 1522-2683)
Enhancing Binding Kinetics Using AC Electroosmotic Mixing (Sponsored by State of Pennsylvania) A chief characteristic for all biosensors is detection time. Regardless of other capabilities, (sensitivity, dynamic range, specificity, etc.) poor detection time can dramatically limit the usefulness of any biosensor. In general, the rate-limiting process is the transport of analyte to the transducer surface. In order to enhance the binding kinetics of biosensors electrohydrodynamic (EHD) effects may be utilized to create convective mixing near the surface of the sensor. This mixing will ensure that fresh reagent is continuously delivered to the sensor surface. The EHD mixing device is simple, contains no moving parts, uses very little space and should not affect the sensing capabilities of the transducer. Such an improvement to the detection time can be realized for a wide variety of sensor types (acoustic, optical, thermal…) and can have a great impact on the fields of diagnostics, bio-warfare agent detection and environmental and food monitoring among others. In this project, a thickness shear mode (TSM) sensor and ELISA assay are used as test cases. (Collaborator: Profs. Ryszard Lec and Elisabeth Papazoglou of Biomedical Engineering) R. Hart, R. Lec, and H. Noh, “Enhancement of Fluorescent Heterogeneous Immunoassays with AC Electroosmosis and Dielectrophoresis,” Sensors and Actuators B, 147, 366–375, 2010 (ISSN: 0925-4005) H. Song, Z. Cai, H. Noh, and D. Bennett, “Chaotic Mixing in Microchannels via Low Frequency Switching Transverse Electroosmotic Flow Generated on Integrated Microelectrodes,” Lab Chip, 10, 734–740, 2010 (ISSN: 1473-0189) R. Hart, E. Ergezen R. Lec, and H. Noh, “Improved Protein Detection on an AC Electrokinetic Quartz Crystal Microbalance (EKQCM), Biosensors and Bioelectronics, 26(8), 3391-3397, 2011 (ISSN: 0956-5663) C. Yu, G-B Kim, P. Clark, L. Zubkov, E. Papazoglou, and H. Noh, A Microfabricated Quantum Dot Linked Immuno-Diagnostic Assay (µQLIDA) with an Electrohydrodynamic Mixing Element , Sensors and Actuators B, 209, 722-728, 2015
Microchip Capillary Electrophoresis for Single Cell Analysis Seemingly identical cells are often quite heterogeneous in their chemical composition and biological activity and in the responses to drugs or external stimuli. Conventional biochemical assays that sample thousands of cells ignore the intracellular heterogeneity and thus fail to provide the rich information available when single cells are studied. Accurate analysis of the identity and quantity of proteins within individual cells would unveil numerous molecular pathways involved in metabolic processes and disease progression leading to development of new drugs, and would also enable the detection and identification of rare, abnormal cells in large populations of cells, potentially providing early diagnosis of diseases. Microchip capillary electrophoresis (μCE) is a powerful analytical technique that can provide an accurate molecular analysis of single cells. However, the adoption of μCE in single cell analysis has been hampered by the absence of automated, high-throughput system. The low throughput is mainly due to time-consuming cell handling and processing steps currently followed. The objective of this project is to develop an integrated μCE system for high-throughput, sequential proteomic analysis (> 100 cells/min) of single cells. The proposed integrated system consists of sequential cell delivery, continuous cell lysis, preconcentration of proteins, and effective electrophoretic separation. (Collaborators: Prof. Bahktier Farouk of Mechanical Engineering and Prof. Vanlila Swami of Pathology and Laboratory Medicine Department) D. Lee, B. Farouk, and H. Noh, “3-D Simulation of Electroosmotic Injection and Migration in Microchannels: Effects of Nonrectangular Cross Section,” Separation Science and Technology, 46, 195-204, 2011 (ISSN: 0149-6395) D. Lee, B. Farouk, and H. Noh, “3-D Simulations of Electroosmotic Sample Migration in Microchannels: Effects of Surface and Solution Property Variations,” Separation Science and Technology, 46, 1377-1387, 2011 (ISSN: 0149-6395)
Medical Implants and Neural Probes
Implantable Microdevice for the Treatment of Hydrocephalus (Sponsored by NIH and State of Pennsylvania) Cerebrospinal fluid (CSF) is a water-like fluid produced in the brain that circulates around and protects the brain and spinal cord. It is believed that CSF is absorbed into the superior sagittal sinus through biologic one-way valves called arachnoid villi, which are located in dura mater. Hydrocephalus is an abnormal accumulation of CSF within the subarachnoid space of the brain due to impaired CSF absorption. Hydrocephalus is one of the most frequently encountered problems in Neurosurgery. Currently, hydrocephalus is treated by a surgical procedure, performed by a neurosurgeon, in which a tube called a shunt is placed into the patient's body. The shunt systems for diverting CSF from the intracranial compartment was developed in 1960’s and has remained essentially unchanged for the last 40 years. In this project we attempt to replace the deficient arachnoid villi (AV) that produce the pathologic condition of communicating hydrocephalus with a micro-fabricated device to restore the normal absorptive function. The microfabricated arachnoid villi (MAV) will be implanted against the dura mater. (Collaborator: Dr. Francis Kralick of Neurosurgery @ Hanehmann Hospital) M. Emam, Y. Abashiya, J. Oh, Y. Choi, F. Kralick, and H. Noh, “A Novel Microdevice for the Treatment of Hydrocephalus: Design and Fabrication of an Array of Microvalves and Microneedles,” Microsystems Technologies, Vol.14, No.3, 371-378, 2008. J. Oh, G. Kim, F. Kralick, and H. Noh, “Design and Fabrication of a PDMS/Parylene Microvalve for the Treatment of Hydrocephalus,” Journal of Microelectromechanical Systems, 20(4), 811-818, 2011 (ISSN: 1057-7157) J. Oh, K. Liu, T. Medina, F. Kralick, and H. Noh, A novel microneedle array for the treatment of hydrocephalus, Microsystem Technologies, DOI 10.1007/s00542-013-1988-4, 2013
Flexible Neural Probes for Single Neuron Network and Epidural Stimulation Neural interface technologies are envisioned to facilitate direct connections between the nervous system and external technologies such as limb prosthetics or data acquisition systems for further processing. In amputees, such technologies would provide direct neural control of prosthetic movements and restore sensory feedback by functionally reconnecting damaged efferent motor and afferent sensory pathways. Dr. Yoonsu Choi (Univ. Texas) is one of few researchers in the world who demonstrated selective recording and stimulation on the peripheral nerve system. We are working with him to develop a single neuron network (SNN), which is designed to communicate with individual neurons in the peripheral nerves and neuronal networks in the central and peripheral nervous system (CNS-PNS) for the first time. We are also working with Drs. Karen Moxon (Drexel Bioengineering) and Simon Gistzer (DUCOM) to develop flexible neural probes for epidural stimulation. This is based on a new microfabrication technology for creating flexible Parylene-based microelectrodes that we recently developed. Below are the journal papers we published related to this topic. (Collaborators: Prof. Karen Moxon of Biomedical Engineering, Prof. Simon Giszter of DUCOM, and Prof. Yoonsu Choi of University of Texas) Y. Choi and H. Noh, Peripheral Nerve Regeneration Monitoring Using Multi-layer Microchannel Scaffold, Neural Regeneration Research, 11(3), 422-423, 2016 Y. Kim, J-W. Kim, J. Kim, and M. Noh, A Novel Fabrication Method of Parylene-based Microelectrodes Utilizing Inkjet Printing, Sensors and Actuators B, 238, 862-870, 2017
Microfabrication Technology Development
Excimer Laser Micromachining of MEMS Materials (Sponsored by NSF MRI) Excimer laser machining is a versatile technique for creating 3-D microstructures that are difficult to make using conventional photolithography-based techniques. A broad spectrum of materials including semiconductors, ceramics, metals, and plastics can be processed by excimer laser. In order to optimize the ablation process for micromachining of MEMS materials, it is necessary to perform thorough characterization study and understand the interaction between laser parameters and ablation results of particular materials. We have conducted comprehensive and parametric studies on the process-feature relation of excimer laser machining of MEMS materials using both 248 nm KrF excimer laser and 193 nm ArF excimer laser. The characterization study provided guidelines to identifying optimal process parameters for excimer laser machining of MEMS materials. Below are the journal papers we published related to this topic. K. Liu, Z. Nikolov, J. Oh, and H. Noh, KrF excimer laser micromachining of MEMS materials: characterization and applications, Journal of Micromechanics and Microengineering, 22, 015012, 2012 (ISSN: 1361-6439) K. Liu, Y. Kim, and H. Noh, ArF excimer laser micromachining of MEMS materials: characterization and applications, ASME Journal of Micro and Nano Manufacturing, 2014, 2(2), 021006
Inkjet Printing of Conductive Materials and Pattern Transfer A number of researchers have studied direct printing of ink containing silver nanoparticles on diverse substrates using inkjet printing but few studies have been reported on direct printing of silver ink on PDMS substrate, which is one of the most common substrates in microfluidics and lab-on-a-chip community. Direct printing of conductive solutions on PDMS is challenging due to its elastomeric and hydrophobic nature. We conducted extensive study on direct inkjet printing of micro-scale (40-90 µm) silver electrodes on PDMS. The effect of major printing parameters such as drop spacing (DS), sintering temperature/time, platen temperature, and nozzle temperature have been thoroughly characterized to produce continuous silver line with uniform and minimized line width and to enhance electrical properties of electrodes. We also discovered that the silver patterns printed on PDMS could be flawlessly transferred to Parylene thin film via vapor deposition. We were able to create diverse flexible microelectrode devices using this new technique. Below are the journal papers we published related to this topic. Y. Kim, X. Ren, J. Kim, and H. Noh, Direct Inkjet Printing of Sliver Microelectrodes on Polydimethylsiloxane (PDMS), Journal of Micromechanics and Microengineering, 24:115010, DOI:10.1088/0960-1317/24/11/115010, 2014 Y. Kim, J-W. Kim, J. Kim, and M. Noh, A Novel Fabrication Method of Parylene-based Microelectrodes Utilizing Inkjet Printing, Sensors and Actuators B, 238, 862-870, 2017
Development of Microfluidics Laboratory Modules and Kits (Sponsored by NSF) Microfluidics technology is rapidly spreading and is widely becoming adapted to many areas of industry and research. In spite of the rapidly growing need for both microfluidics technology and a trained workforce, the current undergraduate curricula of most engineering schools are not well prepared to meet the need. Most engineering programs do not offer microfluidics education in their curricula. This is mainly due to (1) lack of faculty expertise, (2) lack of necessary facilities, (3) the very tight curriculum occupied by traditional engineering subjects, and (4) lack of commercially available and affordable educational materials for training and experimentation. The main objective of this project is to develop and test a set of laboratory modules and kits that will allow engineering and science undergraduate students to explore microscale fluid behaviors and microfluidic devices. (Collaborators: Prof. David Wootton of Cooper Union, Prof. Fredricka Reisman of College of Education)
Integration Technologies Lab-on-a-chip systems often require integration of multiple components of different scales (micro to nano, micro to macro, and micro to micro) and different functions (sample preparation to sensor). In order to address the integration needs of our research projects, we developed diverse integration methods for our applications. They include: integration of microchannel and single carbon nanotube; integration of flow mixing and graphen-based chemical sensor; and gas-liquid interface for microfluidic applications using porous PDMS. Below are the journal papers we published related to this topic. J. Oh, G. Kim, D. Mattia, and H. Noh, “A Novel Technique for Fabrication of Micro- and Nanofluidic Device with Embedded Single Carbon Nanotube,” Sensors and Actuators B, 154, 67-72, 2009 (ISSN: 0925-4005) S. Lee, Y-B Kang, W. Jung, Y. Jung, S. Kim, and H. Noh, Flow-induced voltage generation over monolayer graphene in the presence of herringbone grooves, Nanoscale Research Letters, 8:487  DOI:10.1186/1556-276X-8-487, 2013 H-B Seo, Y-S Kwon, J-E Lee, D. Cullen, H. Noh, and M-B Gu, A Novel Reflectance-based Aptasensor Using Gold Nanoparticles for the Detection of Oxytetracycline, Analyst, 2015, Sep 14; 140(19): 6671-5. doi: 10.1039/c5an00726g. X. Ren, K. Liu, Q. Zhang, H. Noh, E. Caglan Kumbur, W. Yuan, J. Zhou, and P. Chong, Design, Fabrication, and Characterization of Archaeal Tetraether Free-Standing Planar Membranes in a PDMS- and PCB-Based Fluidic Platform, ACS Applied Materials and Interfaces 2014, 6, 12618−12628 X. Ren, H. Lu, J. G. Zhou, P. L-G. Chong, W. Yuan, and M. Noh, Porous PDMS as a Gas-Liquid Interface for Microfluidic Applications, Journal of Microelectromechanical Systems (Accepted)