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Jongyoon Han

• Title: Professor
• Department: Department of Electrical Engineering and Computer Science / Biological Engineering

Collaborators

• C. T. Lim, NUS, Singapore
• Peter Preiser, NTU, Singapore
• K. van Vliet, MSE, MIT
• Ming Dao, MSE, MIT
• Linda Griffith, BE, MIT
• Doug Lauffenburger, BE, MIT
• Samuel Lin, BIDMC, Boston
• Emilio Bizzi, BCS, MIT
• Katharina Ribbeck, BE, MIT
• Jacquin Niles, BE, MIT
• Deb Hung, Broad Institute
• Bruce Levy, Brigham and Women’s Hospital
• Rebecca Baron, Brigham and Women’s Hospital
• Shaoyi Jiang, Univ. of Washington

Graduate Students

• Ragheb El Khaja, Research Assistant, BE/ME
• Sha Huang, Research Assistant, EECS
• Rho-Kyun Kwak, Research Assistant, ME
• Lidan Wu, Research Assistant, BE
• Wong Cheng Lee, Research Assistant, NUS Bioengineerig (SMART)
• Chun Ping Lim, Research Assistant, NTU (SMART)
• Tian Fock Kong, Research Assistant, NTU (SMART)
• Tengyang Jing, Research Assistant, NUS (SMART)
• Rou Jun Toh, Research Assistant, NTU (SMART)

Research Staff

• Han Wei Hou, Ph.D.
• Majid Ebrahimi, Ph. D. (SMART)
• Weng Kung Peng, Ph.D. (SMART)
• Van Sang Pham, Ph.D. (SMART)
• Aniruddh Sarkar, Ph.D.
• Sung Hee Ko, Ph.D.
• Bumjoo Kim, Ph.D.

Support Staff

• S. Davco, Administrative Assistant

Publications

Hou, HW, Gan HY, Bhagat AAS, Li LD, Lim CT, Han J. A microfluidics approach towards high-throughput pathogen removal from blood using margination. Biomicrofluidics, 6, 024115, 2012.

Li L, Lieleg O, Jang S, Ribbeck K, Han J. “A microfluidic in vitro system for quantitative study of stomach mucus barrier function,” Lab on a Chip, 12(20), 4017-4079, 2012

Kwak R, Guan G, Peng WK, Han J. “Microscale Electrodialysis: Concentration Profiling and Vortex Visualization,” Desalination, 308, 138-146, 2012.

Ko SH, Song Y-A, Kim SJ, Kim M, Han J, Kang KH. “Nanofluidic Preconcentration Device in a Straight Microchannel Using Ion Concentration Polarization,” Lab on a Chip, 12, 4472-4482, 2012.

Diez-Silva M, Park Y, Huang S, Bow H, Mercereau-Puijalon O, Deplaine G, Lavazec C, Perrot S, Bonnefoy S, Feld MS, Han J, Dao M, Suresh S. “Pf155/RESA protein influences the dynamic microcirculatory behavior of ring-stage Plasmodium falciparum infected red blood cells,” Scientific Reports, 2, 614, 2012.

Guofeng Guan, Chao Yu Peter Chen, Weng Kung Peng, Ali Asgar Bhagat, Chong Jin Ong, Jongyoon Han, “Real-time control of a microfluidic channel for size-independent deformability cytometry,” Journal of Micromechanics and Microengineering, 22(10), 105037, 2012.

Cheow LF, Bow H, Han J. “Continuous-flow biomolecule concentration and detection in a slanted nanofilter array,” Lab on a Chip, 12, 4441-4448, 2012.

Peng WK, Chen L, Han J. “Development of miniaturized, portable magnetic resonance relaxometry system for point-of-care medical diagnosis,” Review of Scientific Instruments, 83(9):095115-095118, 2012.

Sung Jae Kim, Sung Hee Ko, Rhokyun Kwak, Jonathan D. Posner, Kwan Hyoung Kang and Jongyoon Han, “Multi-Vortical Flow Inducing Electrokinetic Instability in Ion Concentration Polarization Layer,” Nanoscale, 4(23):7406-7410, 2012.

Pham SV, Li Z, Lim KM, White JK, Han J., “Direct numerical simulation of electroconvective instability and hysteretic current-voltage response of permselective membrane,” Physical Review E, 86, 046310, 2012.

Wu L, Guan G, Hou H, Bhagat AA, Han J. “Separation of Leukocytes From Blood Using Spiral Channel With Trapezoid Cross-section,” Analytical Chemistry, 84(21), 9324-31, 2012.

Chen, Chia-Hung; Miller, Miles; Sarkar, Aniruddh; Beste, Michael; Isaacson, Keith; Lauffenburger, Douglas; Griffith, Linda; Han, Jongyoon, “Multiplexed Protease Activity Assay for Low Volume Clinical Samples Using Droplet Based Microfluidics and Its Application to Endometriosis,” Journal of the American Chemical Society, 135(5), 1645-1648, 2012.

Sha Huang, Andreas Undisz, Monica Diez-Silva, Hansen Bow, Ming Dao, Jongyoon Han, “Dynamic deformability of Plasmodium falciparum– infected erythrocytes exposed to artesunate in vitro,” Integrative Biology, 5(2), 414-422, 2012.

Bumjoo Kim, Joonseong Heo, Hyukjin J. Kwon, Seong J. Cho, Jongyoon Han, Sung Jae Kim, and Geunbae Lim, “Tunable Ionic Transport for a Triangular Nanochannel in a Polymeric Nanofluidic System,” ACS Nano, 7(1), 740-747, 2013.

Han Wei Hou, Majid Ebrahimi Warkiani, Bee Luan Khoo, Zi Rui Li, Ross A. Soo, Daniel Shao-Weng Tan, Wan-Teck Lim, Jongyoon Han, Ali Asgar. S. Bhagat, Chwee Teck Lim, “Isolation and retrieval of circulating tumor cells using centrifugal forces,” Scientific Reports, 3, 1259, 2013.

Rhokyun Kwak, Van Sang Pham, Kian Meng Lim, Jongyoon Han, “Shear flow of an electrically charged fluid by ion concentration polarization: Scaling laws for convection vortices,” Physical Review Letters, 110(11), 114501, 2013.

Guofeng Guan, Lidan Wu, Ali Asgar Bhagat, Zi Rui Li, Shuzhe Chao, Peter C Y Chen, Chong Jin Ong, Jongyoon Han,  Spiral microchannel with rectangular and trapezoidal cross-sections for size based particle separation, Scientific Reports, 3, 1475, 2013.

Miles Miller, Aaron S. Meyer, Michael T. Beste, Zainab Lasisi, Sonika Reddy, Karen W. Jeng, Chia-Hung Chen, Jongyoon Han, Keith Isaacson, Linda G. Griffith, Douglas A Lauffenburger, “ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling “, Proceedings of the National Academy of Science, accepted for publication, 2013

Sarkar A, Kolitz S, Lauffenburger DA, Han J. “AN INTEGRATED MICROFLUIDIC PROBE FOR MULTIPLEXED SINGLE CELL KINASE KINASE ACTIVITY MEASUREMENT,” MicroTAS 2012; Okinawa, Japan, 2012; pp. 416-418.

Guan G, Bhagat AA, Wu L, Li Z, Ong CJ, Chen PCY, Han J. “HIGH RESOLUTION SIZE BASED MICRO PARTICLE/CELL SEPARATOR WITH TRAPEZOIDAL CROSS SECTION SPIRAL MICROCHANNELS,” MicroTAS 2012; Okinawa, Japan, 2012, p. 518-520.

Wu L, Guan G, Hou HW, Bhagat AAS, Han J. “CONTINUOUS RBC REMOVAL USING SPIRAL MICROCHANNEL WITH TRAPEZOID CROSS-SECTION,”  MicroTAS 2012; Okinawa, Japan, 2012. p. 1099-1101.

Chen C-H, Miller MA, Sarkar A, Beste MT, Lauffenburger DA, Griffith LG, Han J. “HIGH-THROUGHPUT MUTIPLEXED PROTEASE ACTIVITY MEASUREMENT USING A DROPLET BASED MICROFLUIDIC PLATFORM WITH PICOINJECTOR,” MicroTAS 2012; Okinawa, Japan, 2012. p. 1504-1506.

Ha S, Diez-Silva M, Du E, Kim SJ, Han J, Dao M, Chandrakasan AP. “MICROFLUIDIC ELECTRIC IMPEDANCE SPECTROSCOPY FOR MALARIA DIAGNOSIS,”  MicroTAS 2012; Okinawa, Japan2012. p. 1960-1962.

A Novel Microfluidic “Cell-based” Blood Dialysis Platform for Septic Murine Model

• Authors: H. W. Hou, J. Han
• Sponsorship: DARPA

Sepsis is an adverse systemic inflammatory response caused by microbial infection in blood. We have reported a microfluidic approach for removal of microbes and inflammatory cellular components from whole blood, inspired by the in vivo phenomenon of leukocyte margination^[1],^[2]. We also developed a multiplexed blood filtration platform to demonstrate the bacteria removal capability in vivo using a septic mouse model (Figure 1). As blood flows through the margination channel, deformable red blood cells migrate to the axial center (Fahreaus effect), resulting in margination of other cell types towards the sides. Bacteria-depleted blood is collected at the center outlet and returned directly to the animal, as in a complete dialysis circuit. In vitro experiments using human blood spiked with FITC-conjugated Escherichia coli (E. coli) indicated a bacteria removal efficiency of ~70%; inflammatory cellular components (platelets and leukocytes) were also depleted by >70% (Figure 2). To mimic in vivo mouse filtration, a blood sample (~1mL, similar to mouse blood volume) spiked with fluorescent E. coli was subjected to continuous filtration in a closed loop circuit using a peristaltic pump. Experimental data obtained were in good agreement with the Monod kinetics model, achieving ~40% decrease in bacteria concentration after 30 minutes of filtration. The developed technique offers significant advantages: high throughput (~2mL/hr) and label-free separation for non-specific removal of blood-borne pathogens. The device is ideal for the mouse model: the filtration flow rate (90 mL/kg/hr) is comparable to high-volume hemofiltration (45-60 mL/kg/hr) used for humans in clinical settings. Unlike current extracorporeal blood purifications which mostly focus on cytokines removal, we hypothesize that a broad spectrum removal of bacteria and inflammatory cellular components (platelets and leukocytes) could help modulate the host inflammatory response as a blood cleansing method for sepsis treatment.



Figure 1: Schematic illustration of the (A) 3-channel margination microdevice and (B) separation principle at each bifurcation stage. Deformable RBCs migrate axially to the channel center, resulting in margination of other cell types (bacteria, platelets and leukocytes) towards the channel sidewalls while the center outlet collects the bacteria-depleted blood.



Figure 2: (A) Average composite images illustrating margination of FITC-labelled E. coli at each bifurcation stage. (B) Histogram showing the normalized concentration of different cellular components at the filtered centre outlet. (C) Plot indicating the decrease in bacteria concentration over time for 1mL of blood sample at 30 µLmin-1.




1. H. W. Hou, H. Y. Gan, A. A. S. Bhagat, L. D. Li, C. T. Lim, and J. Han, “A microfluidics approach towards high-throughput pathogen removal from blood using margination,” Biomicrofluidics, vol. 6, pp. 024115-024113, 2012. [↩]
2. H. L. Goldsmith and S. Spain, “Margination of leukocytes in blood flow through small tubes ” Microvascular Research, vol. 27, pp. 204-222, 1984. [↩]

Erythrocyte Deformability Correlates to Intracellular Calcium Level

• Authors: S. Huang, J. Han
• Sponsorship: RLE at MIT

Elevated intracellular calcium level ([Ca++]_i) and reduced deformability  in red blood cells (RBCs) are commonly associated with blood-related diseases^[1][2][3] as well as in-vivo ageing^[4]. The correlation between RBC deformability and [Ca++]_i has been established at the bulk level, typically accompanied with changes in ATP level and RBC size^[4]. It is, however, unclear whether changes in RBC deformability would correspond to [Ca++]_i at the single-RBC level.

In this project, we attempt to establish the connection between single RBC deformability and [Ca++]_i using a microfluidic device as described^[5]. Calcium ionophore A23187 was used for calcium loading, creating different levels of [Ca++]_i. RBC deformability is assessed by measuring the microcirculatory velocity of RBCs in a microfluidic device with narrow gaps^[5]. Simultaneous measurement of calcium intensity and transit velocity was performed while an individual RBC traversed the microchannels.



Figure 1. Snapshot of experimental video analyzed Matlab program. Real time flow (left top corner, F) and calcium intensity are tracked simultaneously. Single RBCs transit velocity is then plotted against calcium intensity (right)

1. Chien S (1987) Red cell deformability and its relevance to blood flow. Ann. Rev. Physiol. 49:177-192. [↩]
2. Baskurt OK, et al. (1998) Red Blood Cell Deformability in Sepsis. American Journal of Respiratory and Critical Care Medicine 157(2):421-427. [↩]
3. Dondorp AM, Pongponratn E, & White NJ (2004) Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology. Acta Tropica 89(3):309-317. [↩]
4. Shiga T, Sekiya M, Maeda N, Kon K, & Okazaki M (1985) Cell age-dependent changes in deformability and calcium accumulation of human erythrocytes. Biochimica et Biophysica Acta (BBA) – Biomembranes 814(2):289-299. [↩] [↩]
5. Bow H, et al. (2011) A microfabricated deformability-based flow cytometer with application to malaria. Lab on a Chip 11(6):1065-1073. [↩] [↩]

Continuous RBC Removal Using Spiral Channel with Trapezoidal Cross-section

• Authors: L. Wu, G. Guan, H. W. Hou, A. A. S. Bhagat, J. Han
• Sponsorship: Singapore-MIT Alliance for Research and Technology, DARPA DLT

Red blood cells (RBC) are the most abundant cell component in many biological fluids, including blood, bone marrow aspirate, and peritoneal aspirate. Depletion of contaminating RBCs from those samples is often an indispensable sample preparation step before the application of any clinical and diagnostic tests^[1], while avoiding artificial alteration on the phenotypes of sorted cells is an important criterion for all studies. The achievement of minimal artifact is especially important in the case of removing RBCs from human blood to isolate white blood cells (WBCs), which play a key role in carrying out and mediating the immune response to various pathogens. The information extracted from the isolated WBCs would be meaningful to facilitate disease prognosis only when the key features of WBCs’ original state are not masked by the sample preparation artifacts. However, several cases have been reported that the conventional methodologies for blood cell separation on the macroscale, including differential centrifugation and selective erythrocyte lysis, could result in altered imuno-phenotype^[2] or impaired viability^[3] of the isolated WBCs. Meanwhile, passive continuous microfluidic separation techniques utilizing the size-dependent hydrodynamic effects^[4][5][6] have been considered as an alternative approach to bypass the issues associated with macroscale blood cell separation methods.

In this work, we improved the separation resolution of curvilinear microchannel while maintaining the high-throughput feature by modifying the channel cross-section to be trapezoidal rather than rectangular and demonstrated its ability for efficient RBC depletion from human blood sample with negligible effect on polymorphonuclear leukocyte (PMN) immune-phenotype as compared to selective erythrocyte lysis method^[7]. To our knowledge, this is the first experimental demonstration where the asymmetry velocity field within a trapezoid spiral channel affects the inertial focusing phenomenon, indicating the feasibility of using channel cross-sectional geometry (other than width and depth) as a parameter for optimization of a curvilinear inertial microfluidic sorter.



Figure 1: Design principle of developed size-based sorter for RBC removal. Spiral channel with trapezoid cross-section (500 μm x 70~ 100 μm, W x H) has higher separation resolution than spiral channel with rectangular cross-section (500 μm x 90 μm) of similar dimension. Sample collected from inner outlet of developed trapezoid cross-sectional spiral would be enriched for WBCs.



Figure 2: Device performance on blood sample. (A) Single pass recovery percentage of blood components for sample collected from inner outlet at different hematocrits. (B) Comparison of PMN activation by spiral and other RBC removal techniques, including density centrifugation (MP-RM) and RBC lysis, based on flow cytometry analysis of CD66b+ CD18+ cells.




1. W. G. Guder, S. Narayanan, H. Wisser, and B. Zawra, Samples: From the Patient to the Laboratory: The impact of preanalytical variables on the quality of laboratory results, 1st ed. Darmstadt, Germany: GIT Verlag, 1996. [↩]
2. J. Lundahl, G. Halldén, M. Hallgren, C. M. Sköld, and J. Hed, “Altered expression of CD11b/CD18 and CD62L on human monocytes after cell preparation procedures,” Journal of Immunological Methods, vol. 180, pp. 93-100, 1995. [↩]
3. C. J. van Oss, P. M. Bronson, E. A. Dinolfo, and K. C. Chadha, “Two methods for the removal of erythrocytes from buffy coats for the production of human leukocyte interferon,” Immunological Communications, vol. 10, pp. 549-555, 1981. [↩]
4. H. W. Hou, A. A. S. Bhagat, W. C. Lee, S. Huang, J. Han, and C. T. Lim, “Microfluidic Devices for Blood Fractionation,” Micromachines, vol. 2, pp. 319-343, 2011. [↩]
5. L. R. Huang, E. C. Cox, R. H. Austin, and J. C. Sturm, “Continuous Particle Separation Through Deterministic Lateral Displacement,” Science, vol. 304, pp. 987-990, May 14, 2004. [↩]
6. M. Yamada, M. Nakashima, and M. Seki, “Pinched Flow Fractionation:  Continuous Size Separation of Particles Utilizing a Laminar Flow Profile in a Pinched Microchannel,” Analytical Chemistry, vol. 76, pp. 5465-5471, Sep. 1, 2004. [↩]
7. L. Wu, G. Guan, H. W. Hou, A. A. S. Bhagat, and J. Han, “Separation of Leukocytes from Blood Using Spiral Channel with Trapezoid Cross-section,” Analytical Chemistry, vol. 84, pp. 9324-9331, Nov. 6, 2012. [↩]

Sheared Electroconvective Vortices in Electrodialysis

• Authors: R. Kwak, V. S. Pham, K. M. Lim, J. Han
• Sponsorship: NSF, DARPA, Singapore-MIT Alliance

We consider electroconvective fluid flows initiated by ion concentration polarization (ICP) under pressure-driven shear flow, a scenario found in many electrochemical devices and systems^[1]. Combining scaling analysis, experiment, and numerical modeling, we reveal unique behaviors of ICP under shear flow: unidirectional vortex structure, height selection of the vortex, and vortex advection. Determined by both the external pressure gradient and the electric body force, the dimensionless height of sheared electroconvective vortex is shown to scale as (φ²/ U_HP)^1/3 (φ:electric potential and U_HP: average flow velocity), which is a clear departure from the previous diffusion-drift model prediction^[2]. To the best of our knowledge, this work is the first microscopic characterization of ion concentration polarization under shear flow; it firmly establishes electroconvection as the mechanism for overlimiting current in realistic, large-area ion exchange membrane systems such as electrodialysis. The new scaling law has significant implications for the optimization of electrodialysis and other electrochemical systems. Details of experimental and simulation methods appear in^[3].



Figure 1: Sheared ICP is visualized by showing local ion concentration profiles (Figures 1(a) and (c)) and EC vortices (Figures 1(b) and (d)) from experiment (at voltage V=10 V and average flow velocity UHP = 0.83 mm/s (flow rate Q=10 µL/min) (Figure 1(a-b)) and simulation (at V= 25V0 and UHP= 80U0, where V0 =25 mV and U0 =29.66 µm/s) (Figure 1(c-d)). Cation exchange membrane (CEM) (anion exchange membrane (AEM)) is located at lower (upper) side of the channel, and ratio of channel width to length is 1:5 in both experiment and simulation. In the experiment, local ion concentration was tracked with 10-µM Rhodamine 6G (R6G), and circular depletion boundary layers dbl are observed as a dark region caused by depletion of R6G (Figure 2(a)); in simulation, ion depletion is represented as a blue region (Figure 2(c)). Fluid flows were visualized by stacking time-lapse images of 10-µm polystyrene (PS) beads (Figure 2(b)). Vortex evolution is clearly visualized at entrance region in experiment and simulation (yellow and white dotted lines).



Figure 2: Dimensionless thickness of EC vortex zone dec/w plotted against the scaling factor (φ2/ UHP)1/3 at various applied voltages and flow rates for both experiment (V = 4-20 V and Q= 5-50 µL/min (UHP =0.42-4.17 mm/s)) and simulation (V=21V0-41V0 and UHP=60U0-120U0, where V0 =25 mV and U0 =29.66 µm/s). Dotted lines are the best fitting straight lines for two different sets of experiment data on CEM and AEM, and one set of simulation data.




1. R. Kwak, G. Guan, W. K. Peng, and J. Han, “Microscale electrodialysis: Concentration profiling and vortex visualization,” Desalination, vol. 308, pp. 138-146, Jan. 2013. [↩]
2. R. F. Probstein, Physicochemical Hydrodynamics: An Introduction, Wiley-Interscience, 2003. [↩]
3. R. Kwak, V. S. Pham, K. M. Lim, and J. Han, “Shear Flow of an Electrically Charged Fluid by Ion Concentration Polarization: Scaling Laws for Electroconvective Vortices,” Physical Review Letters, vol. 110, pp. 114501, Mar. 2013. [↩]

Electro-chemical Stimulation of Neuromuscular Systems Using Ion-selective Membranes

• Authors: R. El Khaja, J. Han
• Sponsorship: MIT, Beth Israel Deaconess Medical Center

Spinal cord injury (SCI) leads to paralysis, decrease in quality of life, and high lifetime medical costs. Direct nerve functional electrical stimulation (FES) induces muscles to contract by electrically stimulating nerves, and it shows promise for clinical applications in restoring muscle function in SCI. FES is limited by the lack of graded response in muscle contraction and by high fatigability due to the reversal of the order in which motor units are recruited. Previous work showed that ion-selective membranes can be used to modulate Ca²⁺ ions in-situ, decreasing the current threshold for nerve stimulation and eliciting a more graded muscle contraction response¹. This work has developed polyimide-based cuff ion-selective electrodes to enable the future application of this technique in-vivo. The developed electrodes are flexible, elastic, and conductive. In-vitro tests of the electrodes by stimulation of frog sciatic nerve reproduced the decrease in the stimulation current threshold, which had been observed in planar glass-based electrodes, in the flexible polyimide-based electrodes.  Additionally, cuffing the stimulated nerves with ion-selective electrodes was more effective at decreasing current threshold than planar stimulation. This work also analyzed data on twitch width, contraction time, and relaxation time to infer effects of ion-selective electrodes on recruitment order. Stimulation with the ion-selective electrodes had higher twitch width, contraction time, and relaxation time than traditional electrical stimulation at all force levels. The difference was particularly high at low force levels, indicating an effect of calcium ion depletion on recruitment order^[1].

1. Y. A. Song, R. Melik, A. N. Rabie, et al. “Electrochemical activation and inhibition of neuromuscular systems through modulation of ion concentrations with ion-selective membranes.” Nature Materials. vol. 10, pp. 980-986, Oct. 2011. [↩]