Seong Young Ko

New paradigm for tumor theranostic methodology using bacteria-based microrobot.

We propose a bacteria-based microrobot (bacteriobot) based on a new fusion paradigm for theranostic activities against solid tumors. We develop a bacteriobot using the strong attachment of bacteria to Cy5.5-coated polystyrene microbeads due to the high-affinity interaction between biotin and streptavidin. The chemotactic responses of the bacteria and the bacteriobots to the concentration gradients of lysates or spheroids of solid tumors can be detected as the migration of the bacteria and/or the bacteriobots out of the central region toward the side regions in a chemotactic microfluidic chamber. The bacteriobots showed higher migration velocity toward tumor cell lysates or spheroids than toward normal cells. In addition, when only the bacteriobots were injected to the CT-26 tumor mouse model, Cy5.5 signal was detected from the tumor site of the mouse model. In-vitro and in-vivo tests verified that the bacteriobots had chemotactic motility and tumor targeting ability. The new microrobot paradigm in which bacteria act as microactuators and microsensors to deliver microstructures to tumors can be considered a new theranostic methodology for targeting and treating solid tumors.

Closed-Loop Planar Motion Control of a Steerable Probe With a “Programmable Bevel” Inspired by Nature

Percutaneous intervention has attracted significant interest in recent years, but many of todays needles and catheters can only provide limited control of the trajectory between an entry site and soft tissue target. In order to address this fundamental shortcoming in minimally invasive surgery, we describe the first prototype of a bioinspired multipart probe that can steer along planar trajectories within a compliant medium by means of a novel “programmable bevel,” where the steering angle becomes a function of the offset between interlocked probe segments. A kinematic model of the flexible probe and programmable bevel arrangement is derived. Several parameters of the kinematic model are then calibrated experimentally with a fully functional scaled-up prototype, which is 12 mm in diameter. A closed-loop control strategy with feed-forward and feedback components is then derived and implemented in vitro using an approximate linearization strategy that was first developed for car-like robots. Experimental results demonstrate satisfactory 2-D trajectory following of the prototype (0.68 mm tracking error, with 1.45 mm standard deviation) using an electromagnetic position sensor that is embedded at the tip of the probe.

STING: a soft-tissue intervention and neurosurgical guide to access deep brain lesions through curved trajectories:

Abstract Current trends in surgical intervention favour a minimally invasive approach, in which complex procedures are performed through very small incisions. Specifically, in neurosurgery there is a need for minimally invasive keyhole access, which conflicts with the lack of manoeuvrability of conventional rigid instruments. In an attempt to address this shortcoming, the current state of progress is reported on a soft-tissue intervention and neurosurgical guide (STING) to access deep brain lesions through curved trajectories. The underlying mechanism of motion, based on the reciprocal movement of interlocked probe segments, is biologically inspired and was designed around the unique features of the ovipositor of certain parasitic wasps. Work to date has focused on probe development, low- and high-level control, and trajectory planning. These aspects are described, together with results on each aspect of the work, including biomimetic microtexturing of the probe surface. Progress is very encouraging and demonstrates that forward motion into soft tissue through a reciprocating mechanism is indeed viable and can be achieved through a suitable combination of microtexturing and microfabrication techniques.

Motility analysis of bacteria-based microrobot (bacteriobot) using chemical gradient microchamber.

A bacteria‐based microrobot (bacteriobot) was proposed and investigated as a new type of active drug delivery system because of its useful advantages, such as active tumor targeting, bacteria‐mediated tumor diagnosis, and therapy. In this study, we fabricated a bacteriobot with enhanced motility by selective attachment of flagellar bacteria (Salmonella typhimurium). Through selective bovine serum albumin (BSA) pattering on hydrophobic polystyrene (PS) microbeads, many S. typhimurium could be selectively attached only on the unpatterned surface of PS microbead. For the evaluation of the chemotactic motility of the bacteriobot, we developed a microfluidic chamber which can generate a stable concentration gradient of bacterial chemotactic chemicals. Prior to the evaluation of the bacteriobot, we first evaluated the directional chemotactic motility of S. typhimurium using the proposed microfluidic chamber, which contained a bacterial chemo‐attractant (L‐aspartic acid) and a chemo‐repellent (NiSO4), respectively. Compared to density of the control group in the microfluidic chamber without any chemical gradient, S. typhimurium increased by about 16% in the L‐aspartic acid gradient region and decreased by about 22% in the NiSO4 gradient region. Second, we evaluated the bacteriobots directional motility by using this microfluidic chamber. The chemotactic directional motility of the bacteriobot increased by 14% and decreased by 13% in the concentration gradients of L‐aspartic acid and NiSO4, respectively. These results confirm that the bacteriobot with selectively patterned S. typhimurium shows chemotaxis motility very similar to that of S. typhimurium. Moreover, the directional motilities of the bacteria and bacteriobot could be demonstrated quantitatively through the proposed microfluidic chamber. Biotechnol. Bioeng. 2014;111: 134–143.

A hybrid actuated microrobot using an electromagnetic field and flagellated bacteria for tumor‐targeting therapy

In this paper, we propose a new concept for a hybrid actuated microrobot for tumor‐targeting therapy. For drug delivery in tumor therapy, various electromagnetic actuated microrobot systems have been studied. In addition, bacteria‐based microrobot (so‐called bacteriobot), which use tumor targeting and the therapeutic function of the bacteria, has also been proposed for solid tumor therapy. Compared with bacteriobot, electromagnetic actuated microrobot has larger driving force and locomotive controllability due to their position recognition and magnetic field control. However, because electromagnetic actuated microrobot does not have self‐tumor targeting, they need to be controlled by an external magnetic field. In contrast, the bacteriobot uses tumor targeting and the bacterias own motility, and can exhibit self‐targeting performance at solid tumors. However, because the propulsion forces of the bacteria are too small, it is very difficult for bacteriobot to track a tumor in a vessel with a large bloodstream. Therefore, we propose a hybrid actuated microrobot combined with electromagnetic actuation in large blood vessels with a macro range and bacterial actuation in small vessels with a micro range. In addition, the proposed microrobot consists of biodegradable and biocompatible microbeads in which the drugs and magnetic particles can be encapsulated; the bacteria can be attached to the surface of the microbeads and propel the microrobot. We carried out macro‐manipulation of the hybrid actuated microrobot along a desired path through electromagnetic field control and the micro‐manipulation of the hybrid actuated microrobot toward a chemical attractant through the chemotaxis of the bacteria. For the validation of the hybrid actuation of the microrobot, we fabricated a hydrogel microfluidic channel that can generate a chemical gradient. Finally, we evaluated the motility performance of the hybrid actuated microrobot in the hydrogel microfluidic channel. We expect that the hybrid actuated microrobot will be utilized for tumor targeting and therapy in future. Biotechnol. Bioeng. 2015;112: 1623–1631.

Toward a Miniaturized Needle Steering System With Path Planning for Obstacle Avoidance

Percutaneous intervention is among the preferred diagnostic and treatment options in surgery today. Recently, a biologically inspired needle steering system was proposed, where a novel “programmable bevel” is employed to control the tip angle as a function of the offset between interlocked needle segments. The new device, codenamed soft tissue intervention and neurosurgical guide (STING), can steer along arbitrary curvilinear trajectories within a compliant medium, and be controlled by means of an embedded position sensor. In this study, we provide details of our latest attempt to miniaturize the STING, with the design and manufacture of a 4-mm outer diameter (OD) two-part prototype that includes unique features, such as a bespoke trocar and insertion mechanism, which ensure that the segments do not come apart or buckle during the insertion process. It is shown that this prototype can steer around tight bends (down to a radius of curvature of ~70 mm), a performance which is comparable to the best systems in this class. With the need to comply with the specific mechanical constraints of STING, this paper also introduces a novel path planner with obstacle avoidance, which can produce a differentiable trajectory that satisfies constraints on both the maximum curvature of the final trajectory and its derivative. In vitro results in gelatin for the integrated prototype and path planner demonstrate accurate 2-D trajectory following (0.1 mm tracking error, with 0.64 mm standard deviation), with significant scope for future improvements.

Trajectory following for a flexible probe with state/input constraints: An approach based on model predictive control

This paper describes the trajectory following algorithm developed for a bio-inspired flexible probe, the direction of which can be controlled by means of an offset between interlocked probe segments which make up its body. The control approach employs model predictive control (MPC) to explicitly consider input and state constraints which arise from the unique mechanism of motion of the probe. For the sake of fast computation, a tracking error model is modified so that the nonlinear kinematic model of the probe is linearized, and the model is used to convert the optimization problem into a well-known quadratic programming (QP) problem. The input and state constraints are also converted into an inequality to be integrated into the QP problem. Simulated results demonstrate that the linearized tracking error model and the MPC control strategy are appropriate, handling large perturbations robustly, while satisfying all constraints. Experimental results in a gelatine sample, carried out with a 12 mm outer diameter prototype, demonstrate satisfactory two-dimensional trajectory following performance (0.52 mm average tracking error, with 1.49 mm STD). The experimental results also show that, given the probes constraints, the proposed controller provides more robust performance against large insertion perturbations than previously published control strategies developed for the probe.

Active Locomotive Intestinal Capsule Endoscope (ALICE) System: A Prospective Feasibility Study

Owing to the limitations of the conventional flexible endoscopes used in gastrointestinal diagnostic procedures, which cause discomfort and pain in patients, a wireless capsule endoscope has been developed and commercialized. Despite the many advantages of the wireless capsule endoscope, its restricted mobility has limited its use to diagnosis of the esophagus and small intestine only. Therefore, to extend the diagnostic range of the wireless capsule endoscope into the stomach and colon, additional mobility, such as 3-D locomotion, and steering of the capsule endoscope, is necessary. Previously, several researchers reported on the development of mobility mechanisms for the capsule endoscope, but they were unable to achieve adequate degrees of freedom or sufficiently diverse capsule motions. Therefore, we proposed a novel electromagnetic actuation system that can realize 3-D locomotion and steering within the digestive organs. The proposed active locomotion intestinal capsule endoscope (ALICE) consists of five pairs of solenoid components and a capsule endoscope with a permanent magnet. With the magnetic field generated by the solenoid components, the capsule endoscope can perform various movements necessary to the diagnosis of the gastrointestinal tract, such as propulsion in any direction, steering, and helical motion. From the results of a basic locomotion test, ALICE showed a propulsion angle error of less than 4° and a propulsion force of 70 mN. To further validate the feasibility of ALICE as a diagnostic tool, we executed ex vivo testing using small intestine extracted from a cow. Through the basic mobility test and the ex vivo test, we verified ALICEs usefulness as a medical capsule endoscopic system.

Preparation of HIFU-triggered tumor-targeted hyaluronic acid micelles for controlled drug release and enhanced cellular uptake

In this study, a novel type of high intensity focused ultrasound (HIFU)-triggered active tumor-targeting polymeric micelle was prepared and investigated for controlled drug release and enhanced cellular uptake. Amphiphilic hyaluronic acid (HA) conjugates were synthesized to form docetaxel loaded micelles in aqueous conditions with high encapsulation efficiencies of over 80%. The micelle sizes were limited to less than 150nm, and they varied slightly according to the encapsulated drug amount. Modifying the micellar surface modification with polyethylene glycol diamine successfully inhibited premature drug leakage at a certain level, and it can be expected to prolong the circulation time of the particles in blood. In addition, high-intensity focused ultrasound was introduced to control the release of docetaxel from micelles, to which the release behavior of a drug can be tuned. The in-vitro cell cytotoxicity of docetaxel-loaded micelles was verified against CT-26 and MDA-MB-231 cells. The IC50 values of drug-loaded micelles to CT-26 and MDA-MB-231 cells were 1230.2 and 870.9ng/mL, respectively. However, when exposed to HIFU, the values decreased significantly, to 181.9 and 114.3ng/mL, suggesting that HIFU can enhance cell cytotoxicity by triggering the release of a drug from the micelles. Furthermore, cellular uptake tests were conducted via the quantitative analysis of intracellular drug concentration within CT-26 (CD44 negative), MDA-MB-231 (CD44 positive), and MDA-MB-231 (CD44 blocked), and then imaged with coumarin-6 loaded micelles. The results verified that intracellular drug delivery can be enhanced efficiently via the CD44 receptor-mediated endocytosis of HA micelles. Moreover, HIFU enhanced the cellular uptake behavior by altering the permeability of the cell membrane. It was also able to aid with the extravasation of micelles into the interior of tumors, which will be explained in further research. Therefore, the present study demonstrates that the micelles prepared in this study can emerge as promising nanocarriers of chemotherapeutic agents for controlled drug release and tumor targeting in cancer treatment.

Two-dimensional needle steering with a “programmable bevel” inspired by nature: Modeling preliminaries

Percutaneous interventions have attracted significant interest in recent years, but most approaches still rely on straight line trajectories between an entry site and a soft tissue target. Thus, to this day, a flexible probe able to bend along predefined curvilinear trajectories within a highly compliant medium without buckling is still an open research challenge. In this paper, we describe the concept of a “programmable bevel” tip, which is inspired by the ovipositor of certain wasps: the offset between two parts of a probe determines the steering direction of the tip thanks to a set of bevels included at the tip of each segment. A kinematic model of the flexible probe and programmable bevel arrangement is derived. Several parameters of the kinematic model are calibrated experimentally using our first prototype of the flexible probe, codenamed STING. Open- (feed-forward) and closed-loop (feedback) control strategies are then derived and implemented in simulation using the chained form representation, originally developed to control car-like robots. Simulated results demonstrate accurate two-dimensional needle steering in the presence of velocity, position, and initial posture disturbances.