This article has been accepted for publication in a future issue of this journal, but has not been fully edited. Content may change prior to final publication. Citation information: DOI 10.1109/TNB.2015.2402651, IEEE Transactions on NanoBioscience
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Microfluidic-Assisted Fabrication of Flexible and Location Traceable Organo-Motor Kyoung Duck Seo, Byung Kook Kwak, Samuel Sánchez*, and Dong Sung Kim* Abstract—In this paper, we fabricate a flexible and location traceable micro-motor, named organo-motor, assisted by microfluidic devices and with high throughput. The organo-motors are composed of organic hydrogel material, poly (ethylene glycol) diacrylate (PEGDA), which can provide the flexibility of their structure. For spatial and temporal traceability of the organo-motors under magnetic resonance imaging (MRI), superparamagnetic iron oxide nanoparticles (SPION; Fe3O4) were incorporated into the PEGDA microhydrogels. Furthermore, a thin layer of platinum (Pt) was deposited onto one side of the SPION-PEGDA microhydrogels providing geometrical asymmetry and catalytic propulsion in aqueous fluids containing hydrogen peroxide solution, H2O2. Furthermore, the motion of the organo-motor was controlled by small external magnet enabled by the presence of SPION in the motor architecture. Index Terms—Flexible, hydrogel, magnetic resonance imaging, microfluidics, micro-motor, microparticle, organo-motor, poly (ethylene glycol) diacrylate, self-propulsion, superparamagnetic iron oxide nanoparticles.
I. INTRODUCTION
P
olymeric particles with micrometer size have been investigated for a wide range of applications such as cosmetics,[1] adhesive,[2] optical materials,[3] and drug Manuscript received October 15, 2014; revised December 18, 2014; accepted February 05, 2015. Date of publication xx xx, xxxx; date of current version xx xx, xxxx. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP (Nos. 2014R1A2A1A01006527 and 2011-0030075), the Industrial Technology Innovation Program (No. 10048358) funded by the Ministry of Trade, Industry and Energy (MI, Korea), and the European Research Council under the European Union’s Seventh Framework Programme (FP7/20072013)/ERC grant agreement (No. 311529). Asterisk indicates corresponding author; S. Sánchez and D. S. Kim contributed equally to this work. K. D. Seo is with Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, South Korea (e-mail: [email protected]). B. K. Kwak is with Department of Radiology, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 156-755, South Korea (e-mail: [email protected]). *S. Sánchez is with Max Planck Institute for Intelligent Systems, Heisenbergstrasse 3, 70569 Stuttgart, Germany, with Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010, Barcelona, Spain, and with Institut de Bioenginyeria de Catalunya (IBEC), Baldiri I Reixac 10-12, 08028 Barcelona, Spain (e-mail: [email protected]). *D. S. Kim is with Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, South Korea (e-mail: [email protected]). Color versions of one or more of the figures in this paper are available online at http://ieeexplore.ieee.org. Digital Object Identifier xx.xxxx/xxx.xxxx.xxxxxxx
delivery systems.[4] In general, conventional methods including emulsion polymerization[5, 6] have been used for the synthesis of the polymeric microparticles. And the resulting microparticles obtained using abovementioned methods can only be achieved in a wide range of size distribution due to inhomogeneous rupturing of droplets during emulsification. However, certain applications require microparticles with narrow size distribution. For instance, in drug delivery application, the size distribution directly affects to the release kinetics of macromolecules[7] and polydisperse microparticles used as embolic agent for cancer therapy aggregated proximally in cluster which then causes a chronic inflammatory response, whereas monodisperse microparticles allow precise location inside the blood vessel.[8, 9] In recent years, microfluidic systems offer low-cost and easy-to-use platforms for synthesizing microparticles of which size are from 10 to 1,000 m.[10] Since microfluidic systems are characterized by the low Reynolds number flow regime, microfluidic systems allow producing microparticles with narrow size distribution and various morphologies including sphere,[11, 12] Janus,[13, 14] and core-shell structure.[15, 16] Artificial self-propelled nano- and micro-motors, which are inspired by natural biomotors,[17-19] were recently engineered with a rich variety of architectures, such as nanowires,[20-22] microtubes,[23-25] spherical particles,[26-28] helical structures,[29-31] and more.[32-34] Those autonomous micro-motors offer great possibilities for research from fundamental mechanisms of motion at the micro- and nanoscale[35-37] to potential biomedical[38-40] and/or environmental applications.[41-44] However, typical artificial micro-motors are commonly formed by rigid structures and/or based on inorganic materials though micro-motors based on polymeric materials were rarely reported.[45-47] Furthermore, a shortcoming of developed micro-motors is that they are difficult to trace and monitor changes in their location when they are introduced into human body for in vivo biomedical applications. Here, we describe the fabrication of flexible and location traceable micro-motor, named organo-motor, assisted by microfluidic devices and with high throughput. The organo-motors are composed of organic hydrogel material, poly (ethylene glycol) diacrylate (PEGDA), which can provide high degree of flexibility to their structure in contrast to inorganic rigid materials. For spatial and temporal traceability of the organo-motor under magnetic resonance imaging (MRI), superparamagnetic iron oxide nanoparticles (SPION; Fe3O4)
This article has been accepted for publication in a future issue of this journal, but has not been fully edited. Content may change prior to final publication. Citation information: DOI 10.1109/TNB.2015.2402651, IEEE Transactions on NanoBioscience
TNB-00120-2014 were incorporated into the PEGDA microhydrogels. Furthermore, a thin layer of platinum (Pt) was deposited onto one side of the SPION-PEGDA microhydrogels for achieving self-propulsion in aqueous fluids containing hydrogen peroxide solution, H2O2. Furthermore, the motion of the organo-motor was controlled by small external magnet enabled by the presence of SPION in the motor architecture. II. MATERIALS AND METHODS A. Materials Poly (ethylene glycol) diacrylate (PEGDA) (Mw 700) and water-based ferrofluid (EMG 705) for SPION were purchased from Sigma-Aldrich and FerroTec, respectively. Mineral oil was obtained from Alfa Sesar. Abil EM90 (Evonik Industries) and Tegitol type NP-10 (Sigma-Aldrich) were individually used for surfactant for oil and water. For UV polymerization of PEGDA, 4-(2-hydroxyethoxy) phenyl-(2-hydroxy-2-propyl) ketone (Irgacure 2959, BASF) and UV-light source (LC8, Hamamatsu) were introduced. Sylgard 184 silicone elastomer kits, consisted of polydimethylsiloxane (PDMS) pre-polymer and curing agent, were obtained from Dow Corning for PDMS replica molding. All chemicals were used as received without further purification. B. Fabrication of hydrodynamic focusing microfluidic device (HFMD) The HFMD was fabricated using well-known soft lithography procedure.[48] The brief protocol is as follows. Photoresist SU-8 2150 (Microchem Corp.) was spin coated on a silicon wafer to determine the final height of microchannel in the HFMD to be around 150 m. After UV exposure onto the SU-8 coated wafer, SU-8 master mold was fabricated. PDMS pre-polymer and curing agent in a 10:1 weight ratio were homogeneously mixed and gently poured onto the master mold. The master mold with the PDMS mixture was placed in the oven at 65C for 3 hours after degassing process in a vacuum chamber. The HFMD was achieved by aligning and bonding two cured PDMS replicas after air plasma treatment on each surface of the replicas. It should be noted that the realized HFMD was utilized to synthesize the microhydrogels without clogging them in the microchannel. Finally the aligned HFMD was baked for overnight at 65C in order to enhance the bonding strength. C. Synthesis of SPION-PEGDA microhydrogels The synthesis of SPION-PEGDA microhydrogels was conducted with the HFMD. Microdroplets were firstly generated and subsequently polymerized to microhydrogels under the UV light source. Finally, the SPION-PEGDA microhydrogels were collected in a vial, and washed with isopropyl alcohol (IPA) and deionized (DI) water several times. The microhydrogels were collected and stored in water, or dried in the oven for further characterization. The 20 % (v/v) PEGDA microhydrogels with different SPION concentration of 0.01, 0.1, 1, and 3 mM were prepared for the evaluation of MRI traceability under in vivo-mimic phantom condition. In order to find out the effect of PEGDA concentration on MRI traceability
2 with the fixed 1 mM SPION concentration, the MR images of 20 and 50 % (v/v) PEGDA microhydrogels were also compared. D. In vivo-mimic phantom preparation for MRI The half volume of the petri dishes was filled with 2 wt % agarose solution which was heated up to 80C and placed in a refrigerator to be solidified. After then, the SPION-PEGDA microhydrogels were placed on the surface of the agarose gel with tweezers while preventing the air bubble entrapment. Lastly, agarose solution was poured once again into the petri dishes to completely cover the microhydrogels. E. Evaluation criteria The morphology of the microdroplets and microhydrogels was captured from microscope and their diameters were measured by twenty-five images which were arbitrarily selected from the each sample. The scanning electron microscopy (SEM) images of the microhydrogels were taken using a JEOL JSM-6390LA at accelerating voltage of 15 kV after the dying process. To confirm the MRI traceability of the microhydrogels in the in vivo-mimic phantom, MR images were obtained using 3-T scanner (Achieva, Philips Medical System) with three different pulse sequences; T2-weighted image (T2WI), T2*-weighted image (T2*WI) and susceptibility-weighted image (SWI). F. Fabrication of organo-motors We used the microhydrogels with 50 % (v/v) PEGDA with 1 mM SPION concentration that was to be confirmed in MRI traceability for the supporter of organo-motors. Suspension of the microhydrogels was placed onto a glass substrate. After a drying process in the oven at 65C, the monolayer of the microhydrogels was formed. Thereafter, a Pt thin layer was deposited on top of the microhydrogels through sputtering during 45 seconds in the condition of 0.1 mbar, 40 mA. Finally, the organo-motors, which were coated with Pt layer on half-sphere, were gently detached from the substrate. Finally autonomous motion of the organo-motors was observed in 2.5 % (v/v) of H2O2 with 0.4 % (v/v) of water surfactant which acts as fuel of the organo-motors.
III. RESULTS AND DISCUSSION A. SPION-PEGDA microhydrogels PEGDA was selected as base material for the microhydrogels because it is biocompatible and non-immunogenic polymeric material.[49] Moreover, its physical and chemical properties can be easily tailored to suit the individual needs for biomedical applications.[50] Fig. 1(a) shows a schematic diagram of the experimental setup for the synthesis of the SPION-PEGDA microhydrogels in the HFMD. The mixture of SPION-PEGDA solution was used as dispersed phase (in yellow) and mineral oil containing surfactant was used as continuous phase. Surfactant in oil was used to prevent coalescence between the adjacent as-dispersed microdroplets. A small amount of 4-(2-hydroxyethoxy) phenyl-(2-hydroxy-2-propyl) ketone was added in the
This article has been accepted for publication in a future issue of this journal, but has not been fully edited. Content may change prior to final publication. Citation information: DOI 10.1109/TNB.2015.2402651, IEEE Transactions on NanoBioscience
TNB-00120-2014 SPION-PEGDA solution as photoinitiator just before the experiments. Both solutions were introduced into the inlet of the HFMD by syringe pumps (KDS-270, KD Scientific). The SPION-PEGDA solution was broken up into monodisperse microdroplets at the orifice of the HFMD due to force balance between interfacial tension and shear force acting on the dispersed phase by the continuous phase. The HFMD allowed us to successfully obtain monodisperse SPION-PEGDA microdroplets in diameter of around 350 m, shown in Fig. 1(b). Microdroplets were firstly generated and subsequently polymerized to microhydrogels by acrylate free radicals under UV irradiation and a schematic diagram of the SPION-PEGDA microhydrogel is shown in Fig. 1(c). Finally, the scanning electron microscopy (SEM) image of the dried microhydrogels with 50 % (v/v) PEGDA and 1 mM SPION concentration in Fig. 1(d) exhibited typical spherical shapes with a smooth surface.
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C. Visualization of SPION-PEGDA microhydrogels under MRI The purpose of the synthesizing the SPION-PEGDA microhydrogels is to fabricate the in vivo location traceable and self-propelled organo-motor. For the evaluation of MRI traceability of the microhydrogels under in vivo-mimic phantom condition, phantoms were prepared by using agarose gel as shown in Fig. 3(a). It should be noted that agarose gel provides realistic tissue-like signal under MRI. We obtained MR images in T2WI, T2*WI and SWI sequences. Fig. 3(b) shows MR images of the SPION-PEGDA microhydrogels with respect to SPION concentration ranging from 0.01 to 3 mM. For comparison studies, we also synthesized pure PEGDA microhydrogels as control by using similar experimental procedure. Under MRI, black signal matter was observed from the SPION-PEGDA microhydrogels with SPION concentration over 0.1 mM, but nothing was observed for pure and 0.01 mM SPION concentrated microhydrogels under same detecting B. Characterization of SPION-PEGDA microhydrogels Fig. 2(a) shows the morphologies of the SPION conditions. In case of 0.1 mM SPION concentration, no signal (1mM)-PEGDA microdroplets and the microhydrogels at each was obtained with T2WI sequence, whereas the signal was environment; in oil, water, and air, respectively. As mentioned detected in T2*WI and SWI sequences. Black signal intensity earlier, the microdroplets were monodispersely generated in the of MRI was also enhanced when the SPION concentration HFMD and then polymerized to the microhydrogels under UV increased regardless of the sequence of MRI. While keeping the light. After the drying process, the microhydrogels shrunk their same SPION concentration, the black signal intensity of MRI own volume. We did not observe morphological collapse of the was found to be decreasing in the order of SWI, T2*WI, and microhydrogels despite of entirely losing the absorbed water, as T2WI sequences. It may be noted that significantly different revealed in third column of Fig. 2(a). The diameter of the sizes of black spots on the MR images such as 0.01 and 0.1 mM microhydrogels, which were fully swollen in water, was similar in T2*WI sequence indicated the undesirable air bubble to the target diameter obtained in the HFMD in Fig. 2(b). We entrapment during the phantom preparing step. We also also estimated volumetric swelling per unit volume (Sv), which observed that there was no significant difference in size and was defined as Sv= |Vw – Va| / Va, where Vw and Va denote intensity of MRI black signal between 20 and 50 % (v/v) volumes of the microhydrogels at swelling (in water) and dry PEGDA under same 1 mM SPION concentration as shown in (in air) states, respectively. The Sv of SPION (1mM)-PEGDA Fig. 3(c). Noteworthy, the SPION successfully acted as an effective microhydrogels with 20 and 50 % (v/v) was calculated as 475 imaging agent at in vivo-mimic phantom condition, and the and 118 %, respectively. The microhydrogels with 20 % (v/v) PEGDA microhydrogels with SPION concentration over 1 mM PEGDA could contain a much larger amount of water than 50 % were useful in developing a MRI-traceable microhydrogels. (v/v) PEGDA due to the difference of monomer concentration The microhydrogels, for instance, could be applied in the field in the microhydrogels.[51] Consequently, diameter of the of biomedical applications such as MRI-traceable embolic microhydrogels with 20 % (v/v) PEGDA was smaller than 50 % agents. The sizes of the engineered microhydrogels are small (v/v) PEGDA after drying process in air. Fig. 2(c) shows the enough to be injected into the blood vessel via microcatheter flexibility of the microhydrogels with 50 % (v/v) PEGDA and 1 and their narrow size distribution can ensure an accurate mM SPION. The hydrogels showed an elastic deformation occlusion in the target blood vessels. In particular, under mechanical compression and are sustainable under 71 % MRI-traceable microhydrogels will be possible to monitor an deformation of their original structure with any observable embolic site in vivo and their structural change over time after breakage. Furthermore, we confirmed that the Pt coated embolic surgery. [53, 54] microhydrogels for organo-motor can also endure large elastic deformation under mechanical compression (details in SI Fig. D. Self-propelled organo-motor S1). It should be emphasized that such flexibility of the In order to generate active motion of the microhydrogels, we microhydrogels is not achievable in typical micro-motors, for made use of catalytic reactions happening on one side of the instance, Janus motors based on polystyrene[37] or silica microhydrogels. For that purpose, we fabricated Janus particles[26, 52] with platinum cap. The flexibility of the microparticles containing asymmetry in their architecture.[26, microhydrogels is important because of the abilities to deform 37] By integrating self-propelled system into the MRI-traceable their shape, to conform to their surroundings, and to move in microhydrogels, it is envisaged that the organo-motor could unstructured environments when they applied to the have access to hard-to-reach lesion in the human body under micro-motors. MRI-navigation for in vivo biomedical applications such as target drug delivery. Fig. 4(a) shows a schematic diagram of the Janus organo-motor fabricated by depositing a Pt thin film on one side of the SPION-PEGDA microhydrogel. The catalytic chemical reaction between Pt and H2O2, employed as a fuel, can
This article has been accepted for publication in a future issue of this journal, but has not been fully edited. Content may change prior to final publication. Citation information: DOI 10.1109/TNB.2015.2402651, IEEE Transactions on NanoBioscience
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be utilized as a driving force of the self-propelled system. The autonomous propulsion based on oxygen generation is shown in Fig. 4(b) which is time-lapse images of the organo-motor suspended in H2O2 solution at a time interval from 0 to 10 seconds (details in Movie S1). Random motion of the autonomous propulsion due to the large amount of O2 generation from the Pt-coated hemisphere is observed. Since SPION embedded in PEGDA are strongly responsive to the magnetic field, the motion of the developed organo-motor can be easily controlled by introducing a small external magnet, shown in Fig 4(c) (details in Movie S2) and Movie S3. Though the present Pt-coated SPION-PEGDA microhydrogel shows controlled propulsion as the organo-motor, this conceptual self-propelled organo-motor cannot be directly used in in vivo physiological situation because a mechanism of self-propulsion is based on catalytic decomposition of H2O2, whose concentrations are still non-biocompatible for long periods.[55] Future efforts should be devoted to develop biocompatible self-propulsion mechanism, for instance, magnesium oxidation or glucose oxidation via enzymatic reactions for in vivo applications. IV. CONCLUSION We demonstrated the facile, fast and precise microfluidic-enabled engineering of the spherical, flexible and monodisperse SPION-PEGDA microhydrogels. Those organic microparticles, can be located using biomedical technologies such as MRI, and generate self-propulsion as autonomous catalytic motors. The SPION incorporated into the PEGDA play major roles not only as contrast agent in MRI but also for the possibility of the directional controllability of the organo-motor. Reaction between Pt layer coated on one side of the microhydrogels and H2O2 generated oxygen bubbles as propulsion mechanism for the organo-motor. The MRI-traceable microhydrogels could be extended to the field of biomedical applications, such as traceable embolic agents and carrier for drug delivery. Furthermore, the organo-motors enabled us to give the possibility of developing biocompatible and flexible micro-motors compared to the conventional rigid micro-motor. In addition, outer surface of the organo-motor can be easily functionalized with proteins or bioactive material through acrylate group of PEGDA. For the further study, biocompatible self-propulsion mechanism, such as magnesium oxidation or glucose oxidation should be developed to satisfy the requirements of in vivo applications. ACKNOWLEDGMENT This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP (Nos. 2014R1A2A1A01006527 and 2011-0030075), the Industrial Technology Innovation Program (No. 10048358) funded by the Ministry of Trade, Industry and Energy (MI, Korea), and the European Research Council under the European Union’s Seventh Framework Programme (FP7/20072013)/ERC grant agreement (No. 311529). We appreciate helpful technical assistance from Mr. Taewan Kim and Mr. Andrew Choi at the Department of Mechanical
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This article has been accepted for publication in a future issue of this journal, but has not been fully edited. Content may change prior to final publication. Citation information: DOI 10.1109/TNB.2015.2402651, IEEE Transactions on NanoBioscience
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5 [47] V. Magdanz, G. Stoychev, L. Ionov, S. Sanchez, and O. G. Schmidt, "Stimuli-responsive microjets with reconfigurable shape," Angew. Chem. Int. Edit., vol. 53, no. 10, pp. 2673-2677, 2014. [48] D. C. Duffy, J. C. McDonald, O. J. A. Schueller, and G. M. Whitesides, "Rapid prototyping of microfluidic systems in poly(dimethylsiloxane)," Anal. Chem., vol. 70, no. 23, pp. 4974-4984, 1998. [49] S. Sharma, K. C. Popat, and T. A. Desai, "Controlling nonspecific protein interactions in silicon biomicrosystems with nanostructured poly(ethylene glycol) films," Langmuir, vol. 18, no. 23, pp. 8728-8731, 2002. [50] C. S. Bahney, T. J. Lujan, C. W. Hsu, M. Bottlang, J. L. West, and B. Johnstone, "Visible light photoinitiation of mesenchymal stem cell-laden bioresponsive hydrogels," Eur. Cells Mater., vol. 22, pp. 43-55, 2011. [51] N. A. Peppas, J. Z. Hilt, A. Khademhosseini, and R. Langer, "Hydrogels in biology and medicine: from molecular principles to bionanotechnology," Adv. Mater., vol. 18, no. 11, pp. 1345-1360, 2006. [52] W. Gao, A. Pei, X. Feng, C. Hennessy, and J. Wang, "Organized self-assembly of Janus micromotors with hydrophobic hemispheres," J. Am. Chem. Soc., vol. 135, no. 3, pp. 998-1001, 2013. [53] H. S. Lee, E. H. Kim, H. Shao, and B. K. Kwak, "Synthesis of SPIO-chitosan microspheres for MRI-detectable embolotherapy," J. Magn. Magn. Mater., vol. 293, no. 1, pp. 102-105, 2005. [54] M. Killer, E. M. Keeley, G. M. Cruise, A. Schmitt, and M. R. McCoy, "MR imaging of hydrogel filament embolic devices loaded with superparamagnetic iron oxide or gadolinium," Neuroradiology, vol. 53, no. 6, pp. 449-456, 2011. [55] S. Sanchez, A. N. Ananth, V. M. Fomin, M. Viehrig, and O. G. Schmidt, "Superfast motion of catalytic microjet engines at physiological temperature," J. Am. Chem. Soc., vol. 133, no. 38 pp. 14860-14863, 2011.
Kyoung Duck Seo received his B.S. and M.S. degree (Mechanical Engineering) from the POSTECH, Pohang, South Korea, in 2008 and 2010, respectively, where he is currently working toward the Ph. D. degree in Department of Mechanical Engineering at POSTECH. His graduate work focused on synthesis of multi-functional hydrogel microparticles for biomedical applications. Byung Kook Kwak obtained Korean Medical Doctor’s License in 1986, and the M.D. (1986) and Ph.D. degrees (2002) from Chung-Ang University College of Medicine in Seoul, Korea. He had the residentship (1987-1990) and fellowship (1993-1995) in radiology in Chung-Ang University Hospital. From 2002 to 2007, he was an associate professor in interventional radiology in Chung-Ang University Hospital. From 2009 to 2010, he did research for brain tumor treatment with 3-bromopyruvate as a postdoctoral fellowship in Johns Hopkins University Hospital, Baltimore city, MD, USA. From 2007 to present, he is a professor in interventional radiology in Chung-Ang University Hospital. His research interests include molecular imaging of stem cells and device developments in interventional radiology. He has had two experiences of technology transfer to a company developing medical devices. One is a technique of embolic materials made of chitosan microspheres. The other is a radiofrequency energy-emitting microcatheter and guidewire system.
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Samuel Sánchez received the Ph.D. degree in chemistry from the Autonomous University of Barcelona, Barcelona, Spain, in June 2008, developing electrochemical nanobiosensors. In February 2009, he accepted a tenure-track position to work on catalytic nanomotors with the International Research Center for Materials Nanoarchitectonics, National Institute for Materials Science, Ibaraki, Japan. Since May 2010, he has been leading the “Biochemical Nanomembranes” Group with the Institute for Integrative Nanosciences at the Leibniz Institute (IFW), Dresden, Germany. He is currently with the Max Planck Institute for Intelligent Systems, Stuttgart, Germany. His research interests include nanorobotics, biophysics, and integrated biosensors. Dr. Sanchez received the IIN-IFW Award in 2011, the Guinness World Record for the smallest man-made jet engine, and the ERC-Starting Grant 2012 “Lab-in-a-tube and Nanorobotic Biosensors (LT-NRBS).” Dong Sung Kim received all his B.S., M.S., and Ph.D. degrees (Mechanical Engineering) from POSTECH, Pohang, South Korea, in 1999, 2001, and 2005, respectively, developing disposable plastic lab on a chips for blood typing. He is currently an associate professor in the Department of Mechanical Engineering at POSTECH. Previously, he was postdoctoral fellow at POSTECH from 2005-2006. He joined the School of Mechanical Engineering at Chung-Ang University in Korea as a faculty member since 2006. After 4 years in Chung-Ang University as a full-time lecturer and an assistant professor, he came back to POSTECH as a faculty member in 2010. His current research is basically focused on the development of micro/nanoengineered metal molds and precision polymer molding technologies. He is interested in biomedical applications of micro/nano polymer processing, such as polystyrene micro/nanoengineered cell culture platforms, disposable lab on a chip devices, multifunctional stimuli-responsive structures, and electrohydrodynamics.
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Fig. 1. (a) A schematic diagram depicting the principles of the HFMD used in synthesis of the SPION-PEGDA microhydrogels. (b) Monodisperse SPION-PEGDA microdroplets generated at the orifice of the HFMD (dotted region of (a)). (c) Schematic diagram shows the polymerized microhydrogel by acrylate free radicals under UV irradiation (d) SEM image of the microhydrogels demonstrating the typical spherical shapes with a smooth surface.
Fig. 2. (a) Microscopic images for the morphological characteristics of the SPION (1mM)-PEGDA microdroplets and microhydrogels with regard to each environment; in oil, water, and air, respectively. Scale bar is 500 m. (b) The diameters of the SPION (1mM)-PEGDA microhydrogels with respect to PEGDA concentration were plotted. (c) Mechanical compression was applied to the SPION (1 mM)-PEGDA (50 % (v/v)) microhydrogels between two parallel plates and the sustainable flexibility of the microhydrogels was observed without structural breakage. Scale bar is 100 m.
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Fig. 3. (a) In vivo-mimic phantom for evaluating MRI traceability of the SPION-PEGDA microhydrogels were prepared by using agarose gel. (b) MR images of the SPION-PEGDA microhydrogels with respect to SPION concentration ranging from 0.01 to 3 mM. As the SPION concentration was increased, black signal intensity of MRI was enhanced. (c) There was no significant difference in size and intensity of MRI black signal between 20 and 50 % (v/v) PEGDA under same 1 mM SPION concentration.
Fig. 4. (a) A schematic diagram shows the principles of the organo-motor. The Pt coated on half sphere acts as catalyst and the catalytic chemical reaction between Pt and H2O2, can be utilized as a driving force of the self-propelled system. (b) Time-lapse images of the organo-motor suspended in H2O2 illustrate the autonomous propulsion at a time interval from 0 to 10 seconds. Scale bar is 500 m. (c) Time-lapse images represent the directional controllability of the organo-motor with response to small external magnet at a time interval from 0 to 30 seconds. Scale bar is 4 mm.
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Microfluidic-Assisted Fabrication of Flexible and Location Traceable Organo-Motor Kyoung Duck Seo, Byung Kook Kwak, Samuel Sánchez*, and Dong Sung Kim* Abstract—In this paper, we fabricate a flexible and location traceable micro-motor, named organo-motor, assisted by microfluidic devices and with high throughput. The organo-motors are composed of organic hydrogel material, poly (ethylene glycol) diacrylate (PEGDA), which can provide the flexibility of their structure. For spatial and temporal traceability of the organo-motors under magnetic resonance imaging (MRI), superparamagnetic iron oxide nanoparticles (SPION; Fe3O4) were incorporated into the PEGDA microhydrogels. Furthermore, a thin layer of platinum (Pt) was deposited onto one side of the SPION-PEGDA microhydrogels providing geometrical asymmetry and catalytic propulsion in aqueous fluids containing hydrogen peroxide solution, H2O2. Furthermore, the motion of the organo-motor was controlled by small external magnet enabled by the presence of SPION in the motor architecture. Index Terms—Flexible, hydrogel, magnetic resonance imaging, microfluidics, micro-motor, microparticle, organo-motor, poly (ethylene glycol) diacrylate, self-propulsion, superparamagnetic iron oxide nanoparticles.
I. INTRODUCTION
P
olymeric particles with micrometer size have been investigated for a wide range of applications such as cosmetics,[1] adhesive,[2] optical materials,[3] and drug Manuscript received October 15, 2014; revised December 18, 2014; accepted February 05, 2015. Date of publication xx xx, xxxx; date of current version xx xx, xxxx. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP (Nos. 2014R1A2A1A01006527 and 2011-0030075), the Industrial Technology Innovation Program (No. 10048358) funded by the Ministry of Trade, Industry and Energy (MI, Korea), and the European Research Council under the European Union’s Seventh Framework Programme (FP7/20072013)/ERC grant agreement (No. 311529). Asterisk indicates corresponding author; S. Sánchez and D. S. Kim contributed equally to this work. K. D. Seo is with Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, South Korea (e-mail: [email protected]). B. K. Kwak is with Department of Radiology, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 156-755, South Korea (e-mail: [email protected]). *S. Sánchez is with Max Planck Institute for Intelligent Systems, Heisenbergstrasse 3, 70569 Stuttgart, Germany, with Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010, Barcelona, Spain, and with Institut de Bioenginyeria de Catalunya (IBEC), Baldiri I Reixac 10-12, 08028 Barcelona, Spain (e-mail: [email protected]). *D. S. Kim is with Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, South Korea (e-mail: [email protected]). Color versions of one or more of the figures in this paper are available online at http://ieeexplore.ieee.org. Digital Object Identifier xx.xxxx/xxx.xxxx.xxxxxxx
delivery systems.[4] In general, conventional methods including emulsion polymerization[5, 6] have been used for the synthesis of the polymeric microparticles. And the resulting microparticles obtained using abovementioned methods can only be achieved in a wide range of size distribution due to inhomogeneous rupturing of droplets during emulsification. However, certain applications require microparticles with narrow size distribution. For instance, in drug delivery application, the size distribution directly affects to the release kinetics of macromolecules[7] and polydisperse microparticles used as embolic agent for cancer therapy aggregated proximally in cluster which then causes a chronic inflammatory response, whereas monodisperse microparticles allow precise location inside the blood vessel.[8, 9] In recent years, microfluidic systems offer low-cost and easy-to-use platforms for synthesizing microparticles of which size are from 10 to 1,000 m.[10] Since microfluidic systems are characterized by the low Reynolds number flow regime, microfluidic systems allow producing microparticles with narrow size distribution and various morphologies including sphere,[11, 12] Janus,[13, 14] and core-shell structure.[15, 16] Artificial self-propelled nano- and micro-motors, which are inspired by natural biomotors,[17-19] were recently engineered with a rich variety of architectures, such as nanowires,[20-22] microtubes,[23-25] spherical particles,[26-28] helical structures,[29-31] and more.[32-34] Those autonomous micro-motors offer great possibilities for research from fundamental mechanisms of motion at the micro- and nanoscale[35-37] to potential biomedical[38-40] and/or environmental applications.[41-44] However, typical artificial micro-motors are commonly formed by rigid structures and/or based on inorganic materials though micro-motors based on polymeric materials were rarely reported.[45-47] Furthermore, a shortcoming of developed micro-motors is that they are difficult to trace and monitor changes in their location when they are introduced into human body for in vivo biomedical applications. Here, we describe the fabrication of flexible and location traceable micro-motor, named organo-motor, assisted by microfluidic devices and with high throughput. The organo-motors are composed of organic hydrogel material, poly (ethylene glycol) diacrylate (PEGDA), which can provide high degree of flexibility to their structure in contrast to inorganic rigid materials. For spatial and temporal traceability of the organo-motor under magnetic resonance imaging (MRI), superparamagnetic iron oxide nanoparticles (SPION; Fe3O4)
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TNB-00120-2014 were incorporated into the PEGDA microhydrogels. Furthermore, a thin layer of platinum (Pt) was deposited onto one side of the SPION-PEGDA microhydrogels for achieving self-propulsion in aqueous fluids containing hydrogen peroxide solution, H2O2. Furthermore, the motion of the organo-motor was controlled by small external magnet enabled by the presence of SPION in the motor architecture. II. MATERIALS AND METHODS A. Materials Poly (ethylene glycol) diacrylate (PEGDA) (Mw 700) and water-based ferrofluid (EMG 705) for SPION were purchased from Sigma-Aldrich and FerroTec, respectively. Mineral oil was obtained from Alfa Sesar. Abil EM90 (Evonik Industries) and Tegitol type NP-10 (Sigma-Aldrich) were individually used for surfactant for oil and water. For UV polymerization of PEGDA, 4-(2-hydroxyethoxy) phenyl-(2-hydroxy-2-propyl) ketone (Irgacure 2959, BASF) and UV-light source (LC8, Hamamatsu) were introduced. Sylgard 184 silicone elastomer kits, consisted of polydimethylsiloxane (PDMS) pre-polymer and curing agent, were obtained from Dow Corning for PDMS replica molding. All chemicals were used as received without further purification. B. Fabrication of hydrodynamic focusing microfluidic device (HFMD) The HFMD was fabricated using well-known soft lithography procedure.[48] The brief protocol is as follows. Photoresist SU-8 2150 (Microchem Corp.) was spin coated on a silicon wafer to determine the final height of microchannel in the HFMD to be around 150 m. After UV exposure onto the SU-8 coated wafer, SU-8 master mold was fabricated. PDMS pre-polymer and curing agent in a 10:1 weight ratio were homogeneously mixed and gently poured onto the master mold. The master mold with the PDMS mixture was placed in the oven at 65C for 3 hours after degassing process in a vacuum chamber. The HFMD was achieved by aligning and bonding two cured PDMS replicas after air plasma treatment on each surface of the replicas. It should be noted that the realized HFMD was utilized to synthesize the microhydrogels without clogging them in the microchannel. Finally the aligned HFMD was baked for overnight at 65C in order to enhance the bonding strength. C. Synthesis of SPION-PEGDA microhydrogels The synthesis of SPION-PEGDA microhydrogels was conducted with the HFMD. Microdroplets were firstly generated and subsequently polymerized to microhydrogels under the UV light source. Finally, the SPION-PEGDA microhydrogels were collected in a vial, and washed with isopropyl alcohol (IPA) and deionized (DI) water several times. The microhydrogels were collected and stored in water, or dried in the oven for further characterization. The 20 % (v/v) PEGDA microhydrogels with different SPION concentration of 0.01, 0.1, 1, and 3 mM were prepared for the evaluation of MRI traceability under in vivo-mimic phantom condition. In order to find out the effect of PEGDA concentration on MRI traceability
2 with the fixed 1 mM SPION concentration, the MR images of 20 and 50 % (v/v) PEGDA microhydrogels were also compared. D. In vivo-mimic phantom preparation for MRI The half volume of the petri dishes was filled with 2 wt % agarose solution which was heated up to 80C and placed in a refrigerator to be solidified. After then, the SPION-PEGDA microhydrogels were placed on the surface of the agarose gel with tweezers while preventing the air bubble entrapment. Lastly, agarose solution was poured once again into the petri dishes to completely cover the microhydrogels. E. Evaluation criteria The morphology of the microdroplets and microhydrogels was captured from microscope and their diameters were measured by twenty-five images which were arbitrarily selected from the each sample. The scanning electron microscopy (SEM) images of the microhydrogels were taken using a JEOL JSM-6390LA at accelerating voltage of 15 kV after the dying process. To confirm the MRI traceability of the microhydrogels in the in vivo-mimic phantom, MR images were obtained using 3-T scanner (Achieva, Philips Medical System) with three different pulse sequences; T2-weighted image (T2WI), T2*-weighted image (T2*WI) and susceptibility-weighted image (SWI). F. Fabrication of organo-motors We used the microhydrogels with 50 % (v/v) PEGDA with 1 mM SPION concentration that was to be confirmed in MRI traceability for the supporter of organo-motors. Suspension of the microhydrogels was placed onto a glass substrate. After a drying process in the oven at 65C, the monolayer of the microhydrogels was formed. Thereafter, a Pt thin layer was deposited on top of the microhydrogels through sputtering during 45 seconds in the condition of 0.1 mbar, 40 mA. Finally, the organo-motors, which were coated with Pt layer on half-sphere, were gently detached from the substrate. Finally autonomous motion of the organo-motors was observed in 2.5 % (v/v) of H2O2 with 0.4 % (v/v) of water surfactant which acts as fuel of the organo-motors.
III. RESULTS AND DISCUSSION A. SPION-PEGDA microhydrogels PEGDA was selected as base material for the microhydrogels because it is biocompatible and non-immunogenic polymeric material.[49] Moreover, its physical and chemical properties can be easily tailored to suit the individual needs for biomedical applications.[50] Fig. 1(a) shows a schematic diagram of the experimental setup for the synthesis of the SPION-PEGDA microhydrogels in the HFMD. The mixture of SPION-PEGDA solution was used as dispersed phase (in yellow) and mineral oil containing surfactant was used as continuous phase. Surfactant in oil was used to prevent coalescence between the adjacent as-dispersed microdroplets. A small amount of 4-(2-hydroxyethoxy) phenyl-(2-hydroxy-2-propyl) ketone was added in the
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TNB-00120-2014 SPION-PEGDA solution as photoinitiator just before the experiments. Both solutions were introduced into the inlet of the HFMD by syringe pumps (KDS-270, KD Scientific). The SPION-PEGDA solution was broken up into monodisperse microdroplets at the orifice of the HFMD due to force balance between interfacial tension and shear force acting on the dispersed phase by the continuous phase. The HFMD allowed us to successfully obtain monodisperse SPION-PEGDA microdroplets in diameter of around 350 m, shown in Fig. 1(b). Microdroplets were firstly generated and subsequently polymerized to microhydrogels by acrylate free radicals under UV irradiation and a schematic diagram of the SPION-PEGDA microhydrogel is shown in Fig. 1(c). Finally, the scanning electron microscopy (SEM) image of the dried microhydrogels with 50 % (v/v) PEGDA and 1 mM SPION concentration in Fig. 1(d) exhibited typical spherical shapes with a smooth surface.
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C. Visualization of SPION-PEGDA microhydrogels under MRI The purpose of the synthesizing the SPION-PEGDA microhydrogels is to fabricate the in vivo location traceable and self-propelled organo-motor. For the evaluation of MRI traceability of the microhydrogels under in vivo-mimic phantom condition, phantoms were prepared by using agarose gel as shown in Fig. 3(a). It should be noted that agarose gel provides realistic tissue-like signal under MRI. We obtained MR images in T2WI, T2*WI and SWI sequences. Fig. 3(b) shows MR images of the SPION-PEGDA microhydrogels with respect to SPION concentration ranging from 0.01 to 3 mM. For comparison studies, we also synthesized pure PEGDA microhydrogels as control by using similar experimental procedure. Under MRI, black signal matter was observed from the SPION-PEGDA microhydrogels with SPION concentration over 0.1 mM, but nothing was observed for pure and 0.01 mM SPION concentrated microhydrogels under same detecting B. Characterization of SPION-PEGDA microhydrogels Fig. 2(a) shows the morphologies of the SPION conditions. In case of 0.1 mM SPION concentration, no signal (1mM)-PEGDA microdroplets and the microhydrogels at each was obtained with T2WI sequence, whereas the signal was environment; in oil, water, and air, respectively. As mentioned detected in T2*WI and SWI sequences. Black signal intensity earlier, the microdroplets were monodispersely generated in the of MRI was also enhanced when the SPION concentration HFMD and then polymerized to the microhydrogels under UV increased regardless of the sequence of MRI. While keeping the light. After the drying process, the microhydrogels shrunk their same SPION concentration, the black signal intensity of MRI own volume. We did not observe morphological collapse of the was found to be decreasing in the order of SWI, T2*WI, and microhydrogels despite of entirely losing the absorbed water, as T2WI sequences. It may be noted that significantly different revealed in third column of Fig. 2(a). The diameter of the sizes of black spots on the MR images such as 0.01 and 0.1 mM microhydrogels, which were fully swollen in water, was similar in T2*WI sequence indicated the undesirable air bubble to the target diameter obtained in the HFMD in Fig. 2(b). We entrapment during the phantom preparing step. We also also estimated volumetric swelling per unit volume (Sv), which observed that there was no significant difference in size and was defined as Sv= |Vw – Va| / Va, where Vw and Va denote intensity of MRI black signal between 20 and 50 % (v/v) volumes of the microhydrogels at swelling (in water) and dry PEGDA under same 1 mM SPION concentration as shown in (in air) states, respectively. The Sv of SPION (1mM)-PEGDA Fig. 3(c). Noteworthy, the SPION successfully acted as an effective microhydrogels with 20 and 50 % (v/v) was calculated as 475 imaging agent at in vivo-mimic phantom condition, and the and 118 %, respectively. The microhydrogels with 20 % (v/v) PEGDA microhydrogels with SPION concentration over 1 mM PEGDA could contain a much larger amount of water than 50 % were useful in developing a MRI-traceable microhydrogels. (v/v) PEGDA due to the difference of monomer concentration The microhydrogels, for instance, could be applied in the field in the microhydrogels.[51] Consequently, diameter of the of biomedical applications such as MRI-traceable embolic microhydrogels with 20 % (v/v) PEGDA was smaller than 50 % agents. The sizes of the engineered microhydrogels are small (v/v) PEGDA after drying process in air. Fig. 2(c) shows the enough to be injected into the blood vessel via microcatheter flexibility of the microhydrogels with 50 % (v/v) PEGDA and 1 and their narrow size distribution can ensure an accurate mM SPION. The hydrogels showed an elastic deformation occlusion in the target blood vessels. In particular, under mechanical compression and are sustainable under 71 % MRI-traceable microhydrogels will be possible to monitor an deformation of their original structure with any observable embolic site in vivo and their structural change over time after breakage. Furthermore, we confirmed that the Pt coated embolic surgery. [53, 54] microhydrogels for organo-motor can also endure large elastic deformation under mechanical compression (details in SI Fig. D. Self-propelled organo-motor S1). It should be emphasized that such flexibility of the In order to generate active motion of the microhydrogels, we microhydrogels is not achievable in typical micro-motors, for made use of catalytic reactions happening on one side of the instance, Janus motors based on polystyrene[37] or silica microhydrogels. For that purpose, we fabricated Janus particles[26, 52] with platinum cap. The flexibility of the microparticles containing asymmetry in their architecture.[26, microhydrogels is important because of the abilities to deform 37] By integrating self-propelled system into the MRI-traceable their shape, to conform to their surroundings, and to move in microhydrogels, it is envisaged that the organo-motor could unstructured environments when they applied to the have access to hard-to-reach lesion in the human body under micro-motors. MRI-navigation for in vivo biomedical applications such as target drug delivery. Fig. 4(a) shows a schematic diagram of the Janus organo-motor fabricated by depositing a Pt thin film on one side of the SPION-PEGDA microhydrogel. The catalytic chemical reaction between Pt and H2O2, employed as a fuel, can
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be utilized as a driving force of the self-propelled system. The autonomous propulsion based on oxygen generation is shown in Fig. 4(b) which is time-lapse images of the organo-motor suspended in H2O2 solution at a time interval from 0 to 10 seconds (details in Movie S1). Random motion of the autonomous propulsion due to the large amount of O2 generation from the Pt-coated hemisphere is observed. Since SPION embedded in PEGDA are strongly responsive to the magnetic field, the motion of the developed organo-motor can be easily controlled by introducing a small external magnet, shown in Fig 4(c) (details in Movie S2) and Movie S3. Though the present Pt-coated SPION-PEGDA microhydrogel shows controlled propulsion as the organo-motor, this conceptual self-propelled organo-motor cannot be directly used in in vivo physiological situation because a mechanism of self-propulsion is based on catalytic decomposition of H2O2, whose concentrations are still non-biocompatible for long periods.[55] Future efforts should be devoted to develop biocompatible self-propulsion mechanism, for instance, magnesium oxidation or glucose oxidation via enzymatic reactions for in vivo applications. IV. CONCLUSION We demonstrated the facile, fast and precise microfluidic-enabled engineering of the spherical, flexible and monodisperse SPION-PEGDA microhydrogels. Those organic microparticles, can be located using biomedical technologies such as MRI, and generate self-propulsion as autonomous catalytic motors. The SPION incorporated into the PEGDA play major roles not only as contrast agent in MRI but also for the possibility of the directional controllability of the organo-motor. Reaction between Pt layer coated on one side of the microhydrogels and H2O2 generated oxygen bubbles as propulsion mechanism for the organo-motor. The MRI-traceable microhydrogels could be extended to the field of biomedical applications, such as traceable embolic agents and carrier for drug delivery. Furthermore, the organo-motors enabled us to give the possibility of developing biocompatible and flexible micro-motors compared to the conventional rigid micro-motor. In addition, outer surface of the organo-motor can be easily functionalized with proteins or bioactive material through acrylate group of PEGDA. For the further study, biocompatible self-propulsion mechanism, such as magnesium oxidation or glucose oxidation should be developed to satisfy the requirements of in vivo applications. ACKNOWLEDGMENT This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP (Nos. 2014R1A2A1A01006527 and 2011-0030075), the Industrial Technology Innovation Program (No. 10048358) funded by the Ministry of Trade, Industry and Energy (MI, Korea), and the European Research Council under the European Union’s Seventh Framework Programme (FP7/20072013)/ERC grant agreement (No. 311529). We appreciate helpful technical assistance from Mr. Taewan Kim and Mr. Andrew Choi at the Department of Mechanical
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Kyoung Duck Seo received his B.S. and M.S. degree (Mechanical Engineering) from the POSTECH, Pohang, South Korea, in 2008 and 2010, respectively, where he is currently working toward the Ph. D. degree in Department of Mechanical Engineering at POSTECH. His graduate work focused on synthesis of multi-functional hydrogel microparticles for biomedical applications. Byung Kook Kwak obtained Korean Medical Doctor’s License in 1986, and the M.D. (1986) and Ph.D. degrees (2002) from Chung-Ang University College of Medicine in Seoul, Korea. He had the residentship (1987-1990) and fellowship (1993-1995) in radiology in Chung-Ang University Hospital. From 2002 to 2007, he was an associate professor in interventional radiology in Chung-Ang University Hospital. From 2009 to 2010, he did research for brain tumor treatment with 3-bromopyruvate as a postdoctoral fellowship in Johns Hopkins University Hospital, Baltimore city, MD, USA. From 2007 to present, he is a professor in interventional radiology in Chung-Ang University Hospital. His research interests include molecular imaging of stem cells and device developments in interventional radiology. He has had two experiences of technology transfer to a company developing medical devices. One is a technique of embolic materials made of chitosan microspheres. The other is a radiofrequency energy-emitting microcatheter and guidewire system.
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Samuel Sánchez received the Ph.D. degree in chemistry from the Autonomous University of Barcelona, Barcelona, Spain, in June 2008, developing electrochemical nanobiosensors. In February 2009, he accepted a tenure-track position to work on catalytic nanomotors with the International Research Center for Materials Nanoarchitectonics, National Institute for Materials Science, Ibaraki, Japan. Since May 2010, he has been leading the “Biochemical Nanomembranes” Group with the Institute for Integrative Nanosciences at the Leibniz Institute (IFW), Dresden, Germany. He is currently with the Max Planck Institute for Intelligent Systems, Stuttgart, Germany. His research interests include nanorobotics, biophysics, and integrated biosensors. Dr. Sanchez received the IIN-IFW Award in 2011, the Guinness World Record for the smallest man-made jet engine, and the ERC-Starting Grant 2012 “Lab-in-a-tube and Nanorobotic Biosensors (LT-NRBS).” Dong Sung Kim received all his B.S., M.S., and Ph.D. degrees (Mechanical Engineering) from POSTECH, Pohang, South Korea, in 1999, 2001, and 2005, respectively, developing disposable plastic lab on a chips for blood typing. He is currently an associate professor in the Department of Mechanical Engineering at POSTECH. Previously, he was postdoctoral fellow at POSTECH from 2005-2006. He joined the School of Mechanical Engineering at Chung-Ang University in Korea as a faculty member since 2006. After 4 years in Chung-Ang University as a full-time lecturer and an assistant professor, he came back to POSTECH as a faculty member in 2010. His current research is basically focused on the development of micro/nanoengineered metal molds and precision polymer molding technologies. He is interested in biomedical applications of micro/nano polymer processing, such as polystyrene micro/nanoengineered cell culture platforms, disposable lab on a chip devices, multifunctional stimuli-responsive structures, and electrohydrodynamics.
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Fig. 1. (a) A schematic diagram depicting the principles of the HFMD used in synthesis of the SPION-PEGDA microhydrogels. (b) Monodisperse SPION-PEGDA microdroplets generated at the orifice of the HFMD (dotted region of (a)). (c) Schematic diagram shows the polymerized microhydrogel by acrylate free radicals under UV irradiation (d) SEM image of the microhydrogels demonstrating the typical spherical shapes with a smooth surface.
Fig. 2. (a) Microscopic images for the morphological characteristics of the SPION (1mM)-PEGDA microdroplets and microhydrogels with regard to each environment; in oil, water, and air, respectively. Scale bar is 500 m. (b) The diameters of the SPION (1mM)-PEGDA microhydrogels with respect to PEGDA concentration were plotted. (c) Mechanical compression was applied to the SPION (1 mM)-PEGDA (50 % (v/v)) microhydrogels between two parallel plates and the sustainable flexibility of the microhydrogels was observed without structural breakage. Scale bar is 100 m.
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Fig. 3. (a) In vivo-mimic phantom for evaluating MRI traceability of the SPION-PEGDA microhydrogels were prepared by using agarose gel. (b) MR images of the SPION-PEGDA microhydrogels with respect to SPION concentration ranging from 0.01 to 3 mM. As the SPION concentration was increased, black signal intensity of MRI was enhanced. (c) There was no significant difference in size and intensity of MRI black signal between 20 and 50 % (v/v) PEGDA under same 1 mM SPION concentration.
Fig. 4. (a) A schematic diagram shows the principles of the organo-motor. The Pt coated on half sphere acts as catalyst and the catalytic chemical reaction between Pt and H2O2, can be utilized as a driving force of the self-propelled system. (b) Time-lapse images of the organo-motor suspended in H2O2 illustrate the autonomous propulsion at a time interval from 0 to 10 seconds. Scale bar is 500 m. (c) Time-lapse images represent the directional controllability of the organo-motor with response to small external magnet at a time interval from 0 to 30 seconds. Scale bar is 4 mm.
