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Ajay Vikram Singh
Postdoctoral Researcher
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Jiang Zhuang
Alumni
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Oncay Yasa
Ph.D. Student
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Pelin Erkoc
Alumni
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Yunus Alapan
Postdoctoral Researcher
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25 results

2018


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Soft erythrocyte-based bacterial microswimmers for cargo delivery

Alapan, Y., Yasa, O., Schauer, O., Giltinan, J., Tabak, A. F., Sourjik, V., Sitti, M.

Science Robotics, 3(17):eaar4423, Science Robotics, April 2018 (article)

Abstract
Bacteria-propelled biohybrid microswimmers have recently shown to be able to actively transport and deliver cargos encapsulated into their synthetic constructs to specific regions locally. However, usage of synthetic materials as cargo carriers can result in inferior performance in load-carrying efficiency, biocompatibility, and biodegradability, impeding clinical translation of biohybrid microswimmers. Here, we report construction and external guidance of bacteria-driven microswimmers using red blood cells (RBCs; erythrocytes) as autologous cargo carriers for active and guided drug delivery. Multifunctional biohybrid microswimmers were fabricated by attachment of RBCs [loaded with anticancer doxorubicin drug molecules and superparamagnetic iron oxide nanoparticles (SPIONs)] to bioengineered motile bacteria, Escherichia coli MG1655, via biotin-avidin-biotin binding complex. Autonomous and on-board propulsion of biohybrid microswimmers was provided by bacteria, and their external magnetic guidance was enabled by SPIONs loaded into the RBCs. Furthermore, bacteria-driven RBC microswimmers displayed preserved deformability and attachment stability even after squeezing in microchannels smaller than their sizes, as in the case of bare RBCs. In addition, an on-demand light-activated hyperthermia termination switch was engineered for RBC microswimmers to control bacteria population after operations. RBCs, as biological and autologous cargo carriers in the biohybrid microswimmers, offer notable advantages in stability, deformability, biocompatibility, and biodegradability over synthetic cargo-carrier materials. The biohybrid microswimmer design presented here transforms RBCs from passive cargo carriers into active and guidable cargo carriers toward targeted drug and other cargo delivery applications in medicine.

link (url) DOI Project Page Project Page [BibTex]

2018

link (url) DOI Project Page Project Page [BibTex]

2017


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Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery

Park, B., Zhuang, J., Yasa, O., Sitti, M.

ACS Nano, 11(9):8910-8923, September 2017, PMID: 28873304 (article)

Abstract
High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single Escherichia coli bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 μm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 μm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance in vitro. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles.

link (url) DOI Project Page Project Page [BibTex]


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Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery

Singh, A. V., Hosseinidoust, Z., Park, B., Yasa, O., Sitti, M.

ACS Nano, 0(0):null, 2017, PMID: 28858477 (article)

Abstract
Biohybrid cell-driven microsystems offer unparalleled possibilities for realization of soft microrobots at the micron scale. Here, we introduce a bacteria-driven microswimmer that combines the active locomotion and sensing capabilities of bacteria with the desirable encapsulation and viscoelastic properties of a soft double-micelle microemulsion for active transport and delivery of cargo (e.g., imaging agents, genes, and drugs) to living cells. Quasi-monodisperse double emulsions were synthesized with an aqueous core that encapsulated the fluorescence imaging agents, as a proof-of-concept cargo in this study, and an outer oil shell that was functionalized with streptavidin for specific and stable attachment of biotin-conjugated Escherichia coli. Motile bacteria effectively propelled the soft microswimmers across a Transwell membrane, actively delivering imaging agents (i.e., dyes) encapsulated inside of the micelles to a monolayer of cultured MCF7 breast cancer and J744A.1 macrophage cells, which enabled real-time, live-cell imaging of cell organelles, namely mitochondria, endoplasmic reticulum, and Golgi body. This in vitro model demonstrates the proof-of-concept feasibility of the proposed soft microswimmers and offers promise for potential biomedical applications in active and/or targeted transport and delivery of imaging agents, drugs, stem cells, siRNA, and therapeutic genes to live tissue in in vitro disease models (e.g., organ-on-a-chip devices) and stagnant or low-flow-velocity fluidic regions of the human body.

link (url) DOI Project Page Project Page [BibTex]


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Magnetotactic Bacteria Powered Biohybrids Target E. coli Biofilms

Stanton, M. M., Park, B., Vilela, D., Bente, K., Faivre, D., Sitti, M., Sánchez, S.

ACS Nano, 0(0):null, September 2017, PMID: 28933815 (article)

Abstract
Biofilm colonies are typically resistant to general antibiotic treatment and require targeted methods for their removal. One of these methods includes the use of nanoparticles as carriers for antibiotic delivery, where they randomly circulate in fluid until they make contact with the infected areas. However, the required proximity of the particles to the biofilm results in only moderate efficacy. We demonstrate here that the nonpathogenic magnetotactic bacteria Magnetosopirrillum gryphiswalense (MSR-1) can be integrated with drug-loaded mesoporous silica microtubes to build controllable microswimmers (biohybrids) capable of antibiotic delivery to target an infectious biofilm. Applying external magnetic guidance capability and swimming power of the MSR-1 cells, the biohybrids are directed to and forcefully pushed into matured Escherichia coli (E. coli) biofilms. Release of the antibiotic, ciprofloxacin, is triggered by the acidic microenvironment of the biofilm, ensuring an efficient drug delivery system. The results reveal the capabilities of a nonpathogenic bacteria species to target and dismantle harmful biofilms, indicating biohybrid systems have great potential for antibiofilm applications.

link (url) DOI Project Page Project Page [BibTex]

link (url) DOI Project Page Project Page [BibTex]


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Biohybrid microtube swimmers driven by single captured bacteria

Stanton, M. M., Park, B., Miguel-López, A., Ma, X., Sitti, M., Sánchez, S.

small, 13(19), March 2017 (article)

Abstract
Bacteria biohybrids employ the motility and power of swimming bacteria to carry and maneuver microscale particles. They have the potential to perform microdrug and cargo delivery in vivo, but have been limited by poor design, reduced swimming capabilities, and impeded functionality. To address these challenge, motile Escherichia coli are captured inside electropolymerized microtubes, exhibiting the first report of a bacteria microswimmer that does not utilize a spherical particle chassis. Single bacterium becomes partially trapped within the tube and becomes a bioengine to push the microtube though biological media. Microtubes are modified with “smart” material properties for motion control, including a bacteria-attractant polydopamine inner layer, addition of magnetic components for external guidance, and a biochemical kill trigger to cease bacterium swimming on demand. Swimming dynamics of the bacteria biohybrid are quantified by comparing “length of protrusion” of bacteria from the microtubes with respect to changes in angular autocorrelation and swimmer mean squared displacement. The multifunctional microtubular swimmers present a new generation of biocompatible micromotors toward future microbiorobots and minimally invasive medical applications.

DOI Project Page Project Page [BibTex]


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Bioadhesive Bacterial Microswimmers for Targeted Drug Delivery in the Urinary and Gastrointestinal Tracts

Mostaghaci, B., Yasa, O., Zhuang, J., Sitti, M.

Advanced Science, May 2017 (article)

Abstract
Bacteria-driven biohybrid microswimmers (bacteriabots), which integrate motile bacterial cells and functional synthetic cargo parts (e.g., microparticles encapsulating drug), are recently studied for targeted drug delivery. However, adhesion of such bacteriabots to the tissues on the site of a disease (which can increase the drug delivery efficiency) is not studied yet. Here, this paper proposes an approach to attach bacteriabots to certain types of epithelial cells (expressing mannose on the membrane), based on the affinity between lectin molecules on the tip of bacterial type I pili and mannose molecules on the epithelial cells. It is shown that the bacteria can anchor their cargo particles to mannose-functionalized surfaces and mannose-expressing cells (ATCC HTB-9) using the lectin–mannose bond. The attachment mechanism is confirmed by comparing the adhesion of bacteriabots fabricated from bacterial strains with or without type I pili to mannose-covered surfaces and cells. The proposed bioadhesive motile system can be further improved by expressing more specific adhesion moieties on the membrane of the bacteria.

DOI Project Page [BibTex]


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Propulsion and Chemotaxis in Bacteria-Driven Microswimmers

Zhuang, J., Park, B., Sitti, M.

Advanced Science, May 2017 (article)

Abstract
Despite the large body of experimental work recently on biohybrid microsystems, few studies have focused on theoretical modeling of such systems, which is essential to understand their underlying functioning mechanisms and hence design them optimally for a given application task. Therefore, this study focuses on developing a mathematical model to describe the 3D motion and chemotaxis of a type of widely studied biohybrid microswimmer, where spherical microbeads are driven by multiple attached bacteria. The model is developed based on the biophysical observations of the experimental system and is validated by comparing the model simulation with experimental 3D swimming trajectories and other motility characteristics, including mean squared displacement, speed, diffusivity, and turn angle. The chemotaxis modeling results of the microswimmers also agree well with the experiments, where a collective chemotactic behavior among multiple bacteria is observed. The simulation result implies that such collective chemotaxis behavior is due to a synchronized signaling pathway across the bacteria attached to the same microswimmer. Furthermore, the dependencies of the motility and chemotaxis of the microswimmers on certain system parameters, such as the chemoattractant concentration gradient, swimmer body size, and number of attached bacteria, toward an optimized design of such biohybrid system are studied. The optimized microswimmers would be used in targeted cargo, e.g., drug, imaging agent, gene, and RNA, transport and delivery inside the stagnant or low-velocity fluids of the human body as one of their potential biomedical applications.

DOI Project Page Project Page [BibTex]

2016


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Bacteria-Driven Particles: Patterned and Specific Attachment of Bacteria on Biohybrid Bacteria-Driven Microswimmers (Adv. Healthcare Mater. 18/2016)

Singh, A. V., Sitti, M.

Advanced Healthcare Materials, 5(18):2306-2306, September 2016 (article)

Abstract
On page 2325, Ajay Vikram Singh and Metin Sitti propose a facile surface patterning technique and a specific, strong biotin–streptavidin bonding of bacteria on patterned surfaces to fabricate Janus particles that are propelled by the attached bacteria. Such bacteria-driven Janus microswimmers could be used for future medicine in targeted drug delivery and environmental remediation.

DOI Project Page [BibTex]


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Bioengineered and biohybrid bacteria-based systems for drug delivery

Hosseinidoust, Z., Mostaghaci, B., Yasa, O., Park, B., Singh, A. V., Sitti, M.

Advanced drug delivery reviews, 106, pages: 27-44, Elsevier, November 2016 (article)

Abstract
The use of bacterial cells as agents of medical therapy has a long history. Research that was ignited over a century ago with the accidental infection of cancer patients has matured into a platform technology that offers the promise of opening up new potential frontiers in medical treatment. Bacterial cells exhibit unique characteristics that make them well-suited as smart drug delivery agents. Our ability to genetically manipulate the molecular machinery of these cells enables the customization of their therapeutic action as well as its precise tuning and spatio-temporal control, allowing for the design of unique, complex therapeutic functions, unmatched by current drug delivery systems. Early results have been promising, but there are still many important challenges that must be addressed. We present a review of promises and challenges of employing bioengineered bacteria in drug delivery systems and introduce the biohybrid design concept as a new additional paradigm in bacteria-based drug delivery.

DOI Project Page Project Page [BibTex]

DOI Project Page Project Page [BibTex]


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Chemotaxis of bio-hybrid multiple bacteria-driven microswimmers

Zhuang, J., Sitti, M.

Scientific reports, 6, Nature Publishing Group, March 2016 (article)

Abstract
In this study, in a bio-hybrid microswimmer system driven by multiple Serratia marcescens bacteria, we quantify the chemotactic drift of a large number of microswimmers towards L-serine and elucidate the associated collective chemotaxis behavior by statistical analysis of over a thousand swimming trajectories of the microswimmers. The results show that the microswimmers have a strong heading preference for moving up the L-serine gradient, while their speed does not change considerably when moving up and down the gradient; therefore, the heading bias constitutes the major factor that produces the chemotactic drift. The heading direction of a microswimmer is found to be significantly more persistent when it moves up the L-serine gradient than when it travels down the gradient; this effect causes the apparent heading preference of the microswimmers and is the crucial reason that enables the seemingly cooperative chemotaxis of multiple bacteria on a microswimmer. In addition, we find that their chemotactic drift velocity increases superquadratically with their mean swimming speed, suggesting that chemotaxis of bio-hybrid microsystems can be enhanced by designing and building faster microswimmers. Such bio-hybrid microswimmers with chemotactic steering capability may find future applications in targeted drug delivery, bioengineering, and lab-on-a-chip devices.

DOI Project Page [BibTex]

DOI Project Page [BibTex]

2015


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pH-taxis of biohybrid microsystems

Zhuang, J., Carlsen, R. W., Sitti, M.

Scientific reports, 5, Nature Publishing Group, June 2015 (article)

Abstract
The last decade has seen an increasing number of studies developing bacteria and other cell-integrated biohybrid microsystems. However, the highly stochastic motion of these microsystems severely limits their potential use. Here, we present a method that exploits the pH sensing of flagellated bacteria to realize robust drift control of multi-bacteria propelled microrobots. Under three specifically configured pH gradients, we demonstrate that the microrobots exhibit both unidirectional and bidirectional pH-tactic behaviors, which are also observed in free-swimming bacteria. From trajectory analysis, we find that the swimming direction and speed biases are two major factors that contribute to their tactic drift motion. The motion analysis of microrobots also sheds light on the propulsion dynamics of the flagellated bacteria as bioactuators. It is expected that similar driving mechanisms are shared among pH-taxis, chemotaxis, and thermotaxis. By identifying the mechanism that drives the tactic behavior of bacteria-propelled microsystems, this study opens up an avenue towards improving the control of biohybrid microsystems. Furthermore, assuming that it is possible to tune the preferred pH of bioactuators by genetic engineering, these biohybrid microsystems could potentially be applied to sense the pH gradient induced by cancerous cells in stagnant fluids inside human body and realize targeted drug delivery.

DOI Project Page [BibTex]

2015

DOI Project Page [BibTex]

2014


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Bio-Hybrid Cell-Based Actuators for Microsystems

Carlsen, Rika Wright, Sitti, Metin

Small, 10(19):3831-3851, 2014 (article)

Abstract
As we move towards the miniaturization of devices to perform tasks at the nano and microscale, it has become increasingly important to develop new methods for actuation, sensing, and control. Over the past decade, bio-hybrid methods have been investigated as a promising new approach to overcome the challenges of scaling down robotic and other functional devices. These methods integrate biological cells with artificial components and therefore, can take advantage of the intrinsic actuation and sensing functionalities of biological cells. Here, the recent advancements in bio-hybrid actuation are reviewed, and the challenges associated with the design, fabrication, and control of bio-hybrid microsystems are discussed. As a case study, focus is put on the development of bacteria-driven microswimmers, which has been investigated as a targeted drug delivery carrier. Finally, a future outlook for the development of these systems is provided. The continued integration of biological and artificial components is envisioned to enable the performance of tasks at a smaller and smaller scale in the future, leading to the parallel and distributed operation of functional systems at the microscale.

link (url) DOI Project Page [BibTex]

2014

link (url) DOI Project Page [BibTex]


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Magnetic steering control of multi-cellular bio-hybrid microswimmers

Carlsen, R. W., Edwards, M. R., Zhuang, J., Pacoret, C., Sitti, M.

Lab on a Chip, 14(19):3850-3859, Royal Society of Chemistry, 2014 (article)

Project Page [BibTex]

Project Page [BibTex]


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Analytical modeling and experimental characterization of chemotaxis in serratia marcescens

Zhuang, J., Wei, G., Carlsen, R. W., Edwards, M. R., Marculescu, R., Bogdan, P., Sitti, M.

Physical Review E, 89(5):052704, American Physical Society, 2014 (article)

Project Page [BibTex]

Project Page [BibTex]

2013


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Near and far-wall effects on the three-dimensional motion of bacteria-driven microbeads

Edwards, M. R., Wright Carlsen, R., Sitti, M.

Applied Physics Letters, 102(14):143701, AIP, 2013 (article)

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2013

Project Page [BibTex]

2012


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Chemotactic steering of bacteria propelled microbeads

Kim, D., Liu, A., Diller, E., Sitti, M.

Biomedical microdevices, 14(6):1009-1017, Springer US, 2012 (article)

Project Page [BibTex]

2012

Project Page [BibTex]

2011


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Chemotactic behavior and dynamics of bacteria propelled microbeads

Kim, Dongwook, Liu, Albert, Stitti, Metin

In Intelligent Robots and Systems (IROS), 2011 IEEE/RSJ International Conference on, pages: 1674-1679, 2011 (inproceedings)

Project Page [BibTex]

2011

Project Page [BibTex]


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Micro-scale propulsion using multiple flexible artificial flagella

Singleton, J., Diller, E., Andersen, T., Regnier, S., Sitti, M.

In Intelligent Robots and Systems (IROS), 2011 IEEE/RSJ International Conference on, pages: 1687-1692, 2011 (inproceedings)

Project Page [BibTex]

Project Page [BibTex]


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Modeling of stochastic motion of bacteria propelled spherical microbeads

Arabagi, V., Behkam, B., Cheung, E., Sitti, M.

Journal of Applied Physics, 109(11):114702, AIP, 2011 (article)

Project Page [BibTex]

Project Page [BibTex]

2007


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Bacterial flagella assisted propulsion of patterned latex particles: Effect of particle size

Behkam, B., Sitti, M.

In Nanotechnology, 2007. IEEE-NANO 2007. 7th IEEE Conference on, pages: 723-727, 2007 (inproceedings)

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2007

Project Page [BibTex]

2006


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Towards hybrid swimming microrobots: bacteria assisted propulsion of polystyrene beads

Behkam, B., Sitti, M.

In Engineering in Medicine and Biology Society, 2006. EMBS’06. 28th Annual International Conference of the IEEE, pages: 2421-2424, 2006 (inproceedings)

Project Page [BibTex]

2006

Project Page [BibTex]


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Design methodology for biomimetic propulsion of miniature swimming robots

Behkam, B., Sitti, M.

Trans.-ASME Journal of Dynamic Systems Measurement and Control, 128(1):36, ASME, 2006 (article)

Project Page [BibTex]

Project Page [BibTex]

2005


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Modeling and testing of a biomimetic flagellar propulsion method for microscale biomedical swimming robots

Behkam, B., Sitti, M.

In Proceedings of Advanced Intelligent Mechatronics Conference, pages: 37-42, 2005 (inproceedings)

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2005

Project Page [BibTex]

2004


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E. coli inspired propulsion for swimming microrobots

Behkam, B., Sitti, M.

In ASME 2004 International Mechanical Engineering Congress and Exposition, pages: 1037-1041, 2004 (inproceedings)

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2004

Project Page [BibTex]

2003


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Biomimetic propulsion for a swimming surgical micro-robot

Edd, J., Payen, S., Rubinsky, B., Stoller, M. L., Sitti, M.

In Intelligent Robots and Systems, 2003.(IROS 2003). Proceedings. 2003 IEEE/RSJ International Conference on, 3, pages: 2583-2588, 2003 (inproceedings)

Project Page [BibTex]

2003

Project Page [BibTex]