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2017


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Gene delivery particle engineering strategies for shape-dependent targeting of cells and tissues.

Kozielski, K., Sitti, M.

Current Gene Therapy, 17, 2017 (article)

Abstract
Background: Successful gene delivery requires overcoming both systemic and intracellular obstacles before the nucleic acid cargo can successfully reach its tissue and subcellular target location. Materials & Methods: Non-viral mechanisms to enable targeting while avoiding off-target delivery have arisen via biological, chemical, and physical engineering strategies. Discussion: Herein we will discuss the physical parameters in particle design that promote tissue- and cell-targeted delivery of genetic cargo. We will discuss systemic concerns, such as circulation, tissue localization, and clearance, as well as cell-scale obstacles, such as cellular uptake and nucleic acid packaging. Conclusion: In particular, we will focus on engineering particle shape and size in order to enhance delivery and promote precise targeting. We will also address methods to program or change particle shape in situ using environmentally triggered cues.

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DOI [BibTex]


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Multi-fractal characterization of bacterial swimming dynamics: a case study on real and simulated Serratia marcescens

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

Proceedings of the Royal Society of London A: Mathematical, Physical and Engineering Sciences, 473(2203), The Royal Society, 2017 (article)

Abstract
To add to the current state of knowledge about bacterial swimming dynamics, in this paper, we study the fractal swimming dynamics of populations of Serratia marcescens bacteria both in vitro and in silico, while accounting for realistic conditions like volume exclusion, chemical interactions, obstacles and distribution of chemoattractant in the environment. While previous research has shown that bacterial motion is non-ergodic, we demonstrate that, besides the non-ergodicity, the bacterial swimming dynamics is multi-fractal in nature. Finally, we demonstrate that the multi-fractal characteristic of bacterial dynamics is strongly affected by bacterial density and chemoattractant concentration.

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link (url) DOI [BibTex]

link (url) DOI [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.

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link (url) DOI Project Page [BibTex]


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Mode Evolution in Strongly Coupled Plasmonic Dolmens Fabricated by Templated Assembly

Flauraud, V., Bernasconi, G. D., Butet, J., Mastrangeli, M., Alexander, D. T. L., Martin, O. J. F., Brugger, J.

ACS Photonics, 4(7):1661-1668, 2017 (article)

Abstract
Plasmonic antennas have enabled a wealth of applications that exploit tailored near-fields and radiative properties, further endowed by the bespoke interactions of multiple resonant building blocks. Specifically, when the interparticle distances are reduced to a few nanometers, coupling may be greatly enhanced leading to ultimate near-field intensities and confinement along with a large energy splitting of resonant modes. While this concept is well-known, the fabrication and characterization of suitable multimers with controlled geometries and few-nanometer gaps remains highly challenging. In this article, we present the topographically templated assembly of single-crystal colloidal gold nanorods into trimers, with a dolmen geometry. This fabrication method enables the precise positioning of high-quality nanorods, with gaps as small as 1.5 nm, which permits a gradual and controlled symmetry breaking by tuning the arrangement of these strongly coupled nanostructures. To characterize the fabricated structures, we perform electron energy loss spectroscopy (EELS) near-field hyperspectral imaging and geometrically accurate EELS, plane wave, and eigenmode full-wave computations to reveal the principles governing the electromagnetic response of such nanostructures that have been extensively studied under plane wave excitation for their Fano resonant properties. These experiments track the evolution of the multipolar interactions with high accuracy as the antenna geometry varies. Our results provide new insights in strongly coupled single-crystal building blocks and open news opportunities for the design and fabrication of plasmonic systems.

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link (url) DOI [BibTex]

link (url) DOI [BibTex]


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Recent Advances in Skin Penetration Enhancers for Transdermal Gene and Drug Delivery

Amjadia, M., Mostaghacia, B., Sittia, M.

Current Gene Therapy, 17, 2017 (article)

Abstract
There is a growing interest in transdermal delivery systems because of their noninvasive, targeted, and on-demand delivery of gene and drugs. However, efficient penetration of therapeutic compounds into the skin is still challenging largely due to the impermeability of the outermost layer of the skin, known as stratum corneum. Recently, there have been major research activities to enhance the skin penetration depth of pharmacological agents. This article reviews recent advances in the development of various strategies for skin penetration enhancement. We show that approaches such as ultrasound waves, laser, and microneedle patches have successfully been employed to physically disrupt the stratum corneum structure for enhanced transdermal delivery. Rather than physical approaches, several non-physical route have also been utilized for efficient transdermal delivery across the skin barrier. Finally, we discuss some clinical applications of transdermal delivery systems for gene and drug delivery. This paper shows that transdermal delivery devices can potentially function for diverse healthcare and medical applications while further investigations are still necessary for more efficient skin penetration of gene and drugs.

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DOI [BibTex]


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A fully dense and globally consistent 3D map reconstruction approach for GI tract to enhance therapeutic relevance of the endoscopic capsule robot

Turan, M., Pilavci, Y. Y., Jamiruddin, R., Araujo, H., Konukoglu, E., Sitti, M.

arXiv preprint arXiv:1705.06524, 2017 (article)

Abstract
In the gastrointestinal (GI) tract endoscopy field, ingestible wireless capsule endoscopy is emerging as a novel, minimally invasive diagnostic technology for inspection of the GI tract and diagnosis of a wide range of diseases and pathologies. Since the development of this technology, medical device companies and many research groups have made substantial progress in converting passive capsule endoscopes to robotic active capsule endoscopes with most of the functionality of current active flexible endoscopes. However, robotic capsule endoscopy still has some challenges. In particular, the use of such devices to generate a precise three-dimensional (3D) mapping of the entire inner organ remains an unsolved problem. Such global 3D maps of inner organs would help doctors to detect the location and size of diseased areas more accurately and intuitively, thus permitting more reliable diagnoses. To our knowledge, this paper presents the first complete pipeline for a complete 3D visual map reconstruction of the stomach. The proposed pipeline is modular and includes a preprocessing module, an image registration module, and a final shape-from-shading-based 3D reconstruction module; the 3D map is primarily generated by a combination of image stitching and shape-from-shading techniques, and is updated in a frame-by-frame iterative fashion via capsule motion inside the stomach. A comprehensive quantitative analysis of the proposed 3D reconstruction method is performed using an esophagus gastro duodenoscopy simulator, three different endoscopic cameras, and a 3D optical scanner.

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link (url) Project Page [BibTex]


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Mobile Microrobotics

Sitti, M.

Mobile Microrobotics, The MIT Press, Cambridge, MA, 2017 (book)

Abstract
Progress in micro- and nano-scale science and technology has created a demand for new microsystems for high-impact applications in healthcare, biotechnology, manufacturing, and mobile sensor networks. The new robotics field of microrobotics has emerged to extend our interactions and explorations to sub-millimeter scales. This is the first textbook on micron-scale mobile robotics, introducing the fundamentals of design, analysis, fabrication, and control, and drawing on case studies of existing approaches. The book covers the scaling laws that can be used to determine the dominant forces and effects at the micron scale; models forces acting on microrobots, including surface forces, friction, and viscous drag; and describes such possible microfabrication techniques as photo-lithography, bulk micromachining, and deep reactive ion etching. It presents on-board and remote sensing methods, noting that remote sensors are currently more feasible; studies possible on-board microactuators; discusses self-propulsion methods that use self-generated local gradients and fields or biological cells in liquid environments; and describes remote microrobot actuation methods for use in limited spaces such as inside the human body. It covers possible on-board powering methods, indispensable in future medical and other applications; locomotion methods for robots on surfaces, in liquids, in air, and on fluid-air interfaces; and the challenges of microrobot localization and control, in particular multi-robot control methods for magnetic microrobots. Finally, the book addresses current and future applications, including noninvasive medical diagnosis and treatment, environmental remediation, and scientific tools.

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Mobile Microrobotics By Metin Sitti - Chapter 1 (PDF) link (url) [BibTex]

Mobile Microrobotics By Metin Sitti - Chapter 1 (PDF) link (url) [BibTex]


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Planning spin-walking locomotion for automatic grasping of microobjects by an untethered magnetic microgripper

Dong, X., Sitti, M.

In 2017 IEEE International Conference on Robotics and Automation (ICRA), pages: 6612-6618, 2017 (inproceedings)

Abstract
Most demonstrated mobile microrobot tasks so far have been achieved via pick-and-placing and dynamic trapping with teleoperation or simple path following algorithms. In our previous work, an untethered magnetic microgripper has been developed which has advanced functions, such as gripping objects. Both teleoperated manipulation in 2D and 3D have been demonstrated. However, it is challenging to control the magnetic microgripper to carry out manipulation tasks, because the grasping of objects so far in the literature relies heavily on teleoperation, which takes several minutes with even a skilled human expert. Here, we propose a new spin-walking locomotion and an automated 2D grasping motion planner for the microgripper, which enables time-efficient automatic grasping of microobjects that has not been achieved yet for untethered microrobots. In its locomotion, the microgripper repeatedly rotates about two principal axes to regulate its pose and move precisely on a surface. The motion planner could plan different motion primitives for grasping and compensate the uncertainties in the motion by learning the uncertainties and planning accordingly. We experimentally demonstrated that, using the proposed method, the microgripper could align to the target pose with error less than 0.1 body length and grip the objects within 40 seconds. Our method could significantly improve the time efficiency of micro-scale manipulation and have potential applications in microassembly and biomedical engineering.

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DOI Project Page [BibTex]

DOI Project Page [BibTex]


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Mobile microrobots for bioengineering applications

Ceylan, H., Giltinan, J., Kozielski, K., Sitti, M.

Lab on a Chip, 17(10):1705-1724, Royal Society of Chemistry, 2017 (article)

Abstract
Untethered micron-scale mobile robots can navigate and non-invasively perform specific tasks inside unprecedented and hard-to-reach inner human body sites and inside enclosed organ-on-a-chip microfluidic devices with live cells. They are aimed to operate robustly and safely in complex physiological environments where they will have a transforming impact in bioengineering and healthcare. Research along this line has already demonstrated significant progress, increasing attention, and high promise over the past several years. The first-generation microrobots, which could deliver therapeutics and other cargo to targeted specific body sites, have just been started to be tested inside small animals toward clinical use. Here, we review frontline advances in design, fabrication, and testing of untethered mobile microrobots for bioengineering applications. We convey the most impactful and recent strategies in actuation, mobility, sensing, and other functional capabilities of mobile microrobots, and discuss their potential advantages and drawbacks to operate inside complex, enclosed and physiologically relevant environments. We lastly draw an outlook to provide directions in the veins of more sophisticated designs and applications, considering biodegradability, immunogenicity, mobility, sensing, and possible medical interventions in complex microenvironments.

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DOI [BibTex]

DOI [BibTex]


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Methods, apparatuses, and systems for micromanipulation with adhesive fibrillar structures

Sitti, M., Mengüç, Y.

US Patent 9,731,422, 2017 (patent)

Abstract
The present invention are methods for fabrication of micro- and/or nano-scale adhesive fibers and their use for movement and manipulation of objects. Further disclosed is a method of manipulating a part by providing a manipulation device with a plurality of fibers, where each fiber has a tip with a flat surface that is parallel to a backing layer, contacting the flat surfaces on an object, moving the object to a new location, then disengaging the tips from the object.

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link (url) [BibTex]


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Surface tension-driven self-alignment

Mastrangeli, M., Zhou, Q., Sariola, V., Lambert, P.

Soft Matter, 13, pages: 304-327, The Royal Society of Chemistry, 2017 (article)

Abstract
Surface tension-driven self-alignment is a passive and highly-accurate positioning mechanism that can significantly simplify and enhance the construction of advanced microsystems. After years of research{,} demonstrations and developments{,} the surface engineering and manufacturing technology enabling capillary self-alignment has achieved a degree of maturity conducive to a successful transfer to industrial practice. In view of this transition{,} a broad and accessible review of the physics{,} material science and applications of capillary self-alignment is presented. Statics and dynamics of the self-aligning action of deformed liquid bridges are explained through simple models and experiments{,} and all fundamental aspects of surface patterning and conditioning{,} of choice{,} deposition and confinement of liquids{,} and of component feeding and interconnection to substrates are illustrated through relevant applications in micro- and nanotechnology. A final outline addresses remaining challenges and additional extensions envisioned to further spread the use and fully exploit the potential of the technique.

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link (url) DOI [BibTex]

link (url) DOI [BibTex]


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A Deep Learning Based 6 Degree-of-Freedom Localization Method for Endoscopic Capsule Robots

Turan, M., Almalioglu, Y., Konukoglu, E., Sitti, M.

arXiv preprint arXiv:1705.05435, 2017 (article)

Abstract
We present a robust deep learning based 6 degrees-of-freedom (DoF) localization system for endoscopic capsule robots. Our system mainly focuses on localization of endoscopic capsule robots inside the GI tract using only visual information captured by a mono camera integrated to the robot. The proposed system is a 23-layer deep convolutional neural network (CNN) that is capable to estimate the pose of the robot in real time using a standard CPU. The dataset for the evaluation of the system was recorded inside a surgical human stomach model with realistic surface texture, softness, and surface liquid properties so that the pre-trained CNN architecture can be transferred confidently into a real endoscopic scenario. An average error of 7.1% and 3.4% for translation and rotation has been obtained, respectively. The results accomplished from the experiments demonstrate that a CNN pre-trained with raw 2D endoscopic images performs accurately inside the GI tract and is robust to various challenges posed by reflection distortions, lens imperfections, vignetting, noise, motion blur, low resolution, and lack of unique landmarks to track.

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link (url) Project Page [BibTex]


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Deep EndoVO: A Recurrent Convolutional Neural Network (RCNN) based Visual Odometry Approach for Endoscopic Capsule Robots

Turan, M., Almalioglu, Y., Araujo, H., Konukoglu, E., Sitti, M.

ArXiv e-prints, 2017 (article)

Abstract
Ingestible wireless capsule endoscopy is an emerging minimally invasive diagnostic technology for inspection of the GI tract and diagnosis of a wide range of diseases and pathologies. Medical device companies and many research groups have recently made substantial progresses in converting passive capsule endoscopes to active capsule robots, enabling more accurate, precise, and intuitive detection of the location and size of the diseased areas. Since a reliable real time pose estimation functionality is crucial for actively controlled endoscopic capsule robots, in this study, we propose a monocular visual odometry (VO) method for endoscopic capsule robot operations. Our method lies on the application of the deep Recurrent Convolutional Neural Networks (RCNNs) for the visual odometry task, where Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) are used for the feature extraction and inference of dynamics across the frames, respectively. Detailed analyses and evaluations made on a real pig stomach dataset proves that our system achieves high translational and rotational accuracies for different types of endoscopic capsule robot trajectories.

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link (url) Project Page [BibTex]


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Localized Single-Cell Lysis and Manipulation Using Optothermally-Induced Bubbles

Fan, Q., Hu, W., Ohta, A. T.

Micromachines, 8(4):121, Multidisciplinary Digital Publishing Institute, 2017 (article)

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[BibTex]

[BibTex]