TARGETED DELIVERY

Mahmut S. Sakar and co-workers, on page 952 combine the design and fabrication of near infrared light (NIR) responsive hydrogel capsules and biocompatible magnetic scaffolds for on-demand, targeted drug and cell delivery. The smart microcapsules encapsulate magnetic alginate microbeads

loaded with biological materials and they can be automatically steered using a magnetic manipulation system. The capsules can be reversibly opened at target locations to release the microbeads using NIR induced heating. Digital artwork created by Rocco Bottani.

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ON An Integrated Microrobotic Platform for On-Demand,

Targeted Therapeutic Interventions

Stefano Fusco , Mahmut Selman Sakar ,* Stephen Kennedy , Christian Peters , Rocco Bottani , Fabian Starsich , Angelo Mao , Georgios A. Sotiriou , Salvador Pané , Sotiris E. Pratsinis , David Mooney , and Bradley J. Nelson

S. Fusco, Dr. M. S. Sakar, R. Bottani, Dr. S. Pané, Prof. B. J. Nelson Institute of Robotics and Intelligent Systems ETH Zurich , Zurich , CH-8092 , Switzerland C. PetersMicro and Nanosystems ETH Zurich , Zurich , CH-8092 , Switzerland F. Starsich, Prof. S. E. Pratsinis Particle Technology Laboratory ETH Zurich , Zurich , CH-8092 , Switzerland E-mail: sakarm@ethz.ch Dr. G. A. Sotiriou Center for Nanotechnology & Nanotoxicology Harvard School of Public Health Boston, MA , 02115 , USA Dr. S. Kennedy, A. Mao, Prof. D. Mooney Wyss Institute for Biologically Inspired Engineering School of Engineering and Applied Sciences Harvard University Cambridge, MA , 02318 , USA

DOI: 10.1002/adma.201304098

Microrobots [ 1 ] for minimally invasive medicine must exhibit locomotion and controlled interaction with their environment. Ideally, microrobots should be able to reach a targeted area, provide treatments and therapies for a desired duration, and, fi nally, be removed or degrade without causing adverse or toxic effects. These tasks could be automated or performed under the direct supervision and control of an external user. Several approaches have been explored for the wireless actuation of microrobots. [ 2,3 ] Among these, magnetic fi elds have been the most widely employed strategy for propulsion, because they do not require special environmental properties such as con-ductivity or transparency. This approach allows for the precise manipulation of magnetic objects toward specifi c locations, and magnetic fi elds are biocompatible even at relatively high fi eld strengths. [ 4 ] Many magnetically actuated microrobots have recently been developed for in vivo biomedical applications including helical swimmers, [ 5 ] microgrippers, [ 6 ] bacteria-based platforms, [ 7 ] and soft microparticles. [ 8 ] Parallel to efforts in robot development, three-dimensional (3D) magnetic manipulation systems [ 4,9,10 ] have been introduced for real-time tracking and automated navigation during medical tasks. In this work, we demonstrate that additional intelligence including sensing and actuation can be instantiated in these microrobots by selecting appropriate materials and methods for the fabrication process.

Stimuli-responsive hydrogels are a class of materials closely resembling biological tissues in their physical and chemical properties. These swollen polymer networks [ 11 ] are of interest

in research and industry for many biomedical applications due to their unique capability of a reversible volume change in response to different stimuli (temperature, pH, ionic strength, etc.). They are used in tissue engineering, [ 12 ] drug and cell delivery, [ 13 ] wound healing [ 14 ] and micro object manipulation. [ 15 ] Additionally, hydrogels can be fabricated that respond to elec-tromagnetic fi elds [ 16,17 ] by inclusion and dispersion of nano-particles and the formation of nanocomposites. [ 18 ] Others have been tailored to recognize and react to particular analytes. [ 19 ] Some groups have investigated their integration into microro-botic platforms [ 3,20 ] or have addressed the related engineering issues. [ 8,21,22 ]

A simple and attractive method to fabricate smart hydrogel based 3D architectures consists of exploiting controlled self-folding behavior. [ 23 ] Folding appears when two coupled layers swell or contract differently in response to a specifi c chemical or physical change, or to a remote actuation. Conventional 2D photolithography, compatible with a large variety of hydrogel monomers and with the inclusion of biological entities has been used in this fi eld to create different structures. Simple tubes [ 24,25 ] or more complicated star-like or sphere-like cap-sules [ 26 ] were proposed for delivery and manipulation tasks, with the possibility to encapsulate cells and drugs directly into the hydrogel matrices and release them by temperature or pH changes.

We report the fabrication of an untethered, self-folding, soft microrobotic platform, in which different functionalities are integrated to achieve targeted, on-demand delivery of biological agents. The microrobot exploits the concept of compartmentali-zation [ 27 ] and consists of a group of magnetic alginate micro-beads encapsulated by a near-infrared light (NIR) responsive hydrogel bilayer structure ( Figure 1 a). The hydrogel bilayer is designed to provide a sealed protected compartment that can be rapidly opened by brief light exposure or by increasing the envi-ronmental temperature over 40 ° C. It encapsulates and concen-trates the loaded microparticles, thus increasing the magnetiza-tion of the device and the signal for tracking. It can be used as a drug delivery platform and activated by NIR (785 nm) laser irradiation. This source of actuation was chosen as a control-lable trigger mechanism, because it can penetrate body tissue without causing damage even at repeated doses. [ 28 ] NIR light sensitive materials were recently presented in the form of gold or graphene nanocomposites for selective cell detection and destruction [ 29,30 ] and drug delivery. [ 31 ]

Hydrogel bilayers with different shapes (from simple tubes to cross-shaped, jellyfi sh-like, and Venus fl ytrap-like struc-tures) were produced following a two-step photolithographic

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procedure. [ 32 ] Hydrogel layers were patterned in an assem-bled chamber composed of a glass photomask and a silicon wafer with thin SU-8 spacers (Figure 1 b). The details of the fabrication process are described in the Supporting Informa-tion (SI). A 10- µ m poly(ethylenglycol) diacrylate (PEGDA) layer was fi rst polymerized and subsequently coupled with a poly(isopropylacrylamide) (NIPAAM) based graphene oxide nanocomposite with no need for alignment due to a preferen-tial adhesion of the hydrogels on the photomask. The thick-ness of this second layer was experimentally fi xed to 30- µ m to ensure complete closure of the microcapsules. The resulting

hydrogel bilayers could be easily released after immersion in water (Figure 1 c), allowing complete reuse of the mask.

Alginate, a natural biodegradable polysaccharide, is often chosen as a gelable polymer for long-term and sustained delivery of both drugs and cells. [ 12,33 ] Alginate gels can be formed in relatively mild pH and temperature conditions using divalent cations as crosslinkers and can be made in a sterile pro-cess allowing for viable cell encapsulation. [ 34 ] Here, iron (II,III) oxide particles (10 wt% Fe 3 O 4 , < 5 µ m diameters) were encap-sulated in alginate matrices resulting in superparamagnetic ferrogel microparticles that allow precise 3D manipulation and control of the full microrobotic platform. A mixture containing dissolved alginate and Fe 3 O 4 nanoparticles was nebulized over a calcium chloride bath (Figure 1 d and SI). Nebulized droplets entered the calcium chloride bath where calcium ions infi ltrated the alginate droplets and served to crosslink alginate polymers (Figure 1 d), thus forming crosslinked alginate microparticles with encapsulated and immobilized iron oxide nanoparticles capable of external magnetic manipulation (Figure 1 d).

We formed the NIR responsive layer by synthesizing and dis-persing graphene oxide (3 wt% of the monomer weight) into the hydrogel solution using tip sonication. Graphene oxide has been recently proposed as a low cost material for NIR hydrogel nanocomposites, [ 16,35 ] ensuring high performance due to its high optical absorbance. The process of oxidation and sonication allowed a stable dispersion of the graphene sheets into the ethyl lactate based solution [ 36 ] composed of NIPAAm, Acrylamide (AAm) (molar ratio 85:15), a low concentration of PEGDA as a crosslinker (molar ratio between monomers and crosslinker was 200:1), and 2,2-dimethoxy-2phenylaceto-phenone (DMPA) as the photoinitiator. A short UV exposure (2 minutes) allowed the formation of highly hydrated hydrogels whose internal structure analyzed by Cryo-SEM revealed a pore size on the order of 100 nm and a uniform distribution of gra-phene sheets on the matrix ( Figure 2 a).

The thermosensitive swelling properties of the two layers were analyzed gravimetrically (Figure 2 b). The full collapse of the thermoresponsive gels was achieved at ! 40 ° C due to copoly-merization with AAm, a hydrophilic monomer. This value, slightly higher than physiological body temperature, ensures that the structure does not respond to physiological body tem-perature conditions and can allow external stimuli to control the actuation of the microrobot. The inclusion of the nano-meter-sized GO sheets, though slightly affecting the swelling ratio properties of the matrix (see SI, Figure S1), allowed their fast and reproducible photo-thermal actuation. The average response time of the layers upon irradiation by a 785 nm laser (power 1.5 W) was on the order of seconds (Figure 2 c). The actuation was fully repeatable (Figure 2 d) upon several cycles of exposure, without any detectable damage to the material. Actuation was achieved even at lower power (up to 0.7 W) with a time response on the order of 1–2 minutes (Figure S5). These values, compatible with previous fi ndings, [ 35 ] can be improved by a straightforward, tuned reduction process on gra-phene oxide [ 37 ] or by covalently crosslinking the sheets with the hydrogel matrix. [ 16 ]

To confi rm the material choice and formulation, we char-acterized the shape change dependence on the external tem-perature of the fi nal microdevices by immersing them in a

Figure 1. a) Hydrogel bilayers are designed to encapsulate and pro-tect magnetic alginate microbeads. The entire microrobot requires two different fabrication procedures. b) Schematic representation of the fabrication method for hydrogel bilayers. c) The 2D shapes drawn on the photomask (up right in the pictures) fold into 3D microstructures, shown in the optical images after release. Scale bar is 200 µ m. The pro-cess exploits backside exposure and the use of anti-adhesive coating to avoid misalignment between the fi rst and the second step. d) Fabrication method of the magnetic alginate beads that are designed for cell delivery. (e) Optical images of the fabricated microparticles. Scale bar is 100 µ m.

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the folded bilayers by mixing them with the hydrogel bilayers in water at elevated temperature levels and allowing subse-quent cooling and folding of the structures ( Figure 3 a). The number of beads trapped and their position and orientation varied depending on the shape of the structures and the size of the microbeads. Structures resembling Venus fl ytraps were able to encapsulate more beads along the dominant axis, while jellyfi sh-like structures folded into a spheroid fi lled with uni-formly distributed beads. The distribution infl uenced the mag-netic properties of the fi nal platform. [ 39 ] In both cases, micro-beads remained inside after complete closure of the hydrogel fi lms and throughout the magnetic manipulation experiments.

Automated, 3D locomotion of the microrobots was achieved by means of a fi ve-degree-of-freedom (5-DOF) electromagnetic manipulation system that was designed for in vivo medical applications (Figure 3 b). The system, called OctoMag, [ 9 ] pro-vides precise positioning under closed-loop control with com-puter vision but can also be used with no visual tracking, relying only on visual feedback to the human operator during direct teleoperation. In previous reports, authors only showed translational motion of magnetic particles mostly using perma-nent magnets. Our magnetic manipulation system is capable

temperature controlled water bath (Figure 2 e). The opening of the bilayers started at around 38 ° C, a temperature slightly below the one observed for the full collapse of the thermore-sponsive layer. A slight increase of AAm mole fraction (5%) in the initial solution was suffi cient to shift this value to 40 ° C. The transition was completed in a few seconds and the same time-scale was found for the NIR light actuation of the microstruc-tures once the laser spot was focused on them. The cytotoxicity of the hydrogel bilayers was also tested. No signifi cant decrease in metabolic activity compared to a control was observed after immersion of fi broblasts into hydrogel-conditioned medium or after direct contact with the structures (Figure S2). For in vivo applications, in addition to biocompatibility, further improve-ments are needed to minimize adverse effects. The fabrica-tion method of hydrogel bilayers is compatible with the use of biodegradable materials, [ 25 ] which could lead to noninvasive material removal after targeted interventions. We could also take advantage of the unique properties of thermoresponsive NIPAAm based layers to modulate surface adhesion properties and avoid a potential foreign body reaction. [ 38 ]

To complete the microrobotic platform, magnetic alginate microparticles were loaded inside the sealed compartment of

Figure 2. Graphene oxide nanocomposite: a) Cryo SEM internal nanomorphology. b) Temperature response and swelling ratio of the two layers. c) Laser sensitivity to IR laser exposure at a power of 1.5 W. d) Representative curve of the temperature change of the double layer as a function of NIR exposure-rest cycles. e) Optical microscope images of temperature dependent unfolding of long venus fl ytrap-like hydrogel bilayers. The closed confi guration at body temperature allows remote actuation in a physiological environment.

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the beads are collected together, the magnetic signal for MRI tracking would be relatively high). We planned an 8-shape trajectory, and the robot was steered by the system along the path multiple times (Video S2).

At rotational magnetic fi eld frequencies lower than 4Hz, the microstructure and the encapsulated microbeads rotated as a whole. However, as the frequency increased, the motion of the microbeads was decoupled from the surrounding microstructure, and they started to move freely inside the bilayers. Even after days inside the hydrogel micro-structures, the alginate beads did not adhere to the internal surface of the bilayers, and we could move them within the confi ned space with rotating magnetic fi elds (Video S3). Exposure to laser irradiation allowed fast unfolding of the structures and sudden release of the particles stored in their internal compartment. More specifi cally, most of the microbeads were released by the rapid con-formal changes of microstructures during unfolding and we completed the release by subsequent external magnetic fi eld stimula-tion (see Figure 3 e and Video S4).

As a proof of concept for a full multi-tasking microrobot, we tested the possibility of loading a model drug on the NIR respon-sive hydrogel, and we investigated the effect of NIR laser exposure on the release. For this purpose, hydrogel disks (diameter 4.5 mm, thickness 2 mm) of the GO thermosensitive layers were immersed into a PBS (pH 7.4) solution of brilliant green (BG, 1 mM), a dye often used as a topical antiseptic. In vitro release of BG was analyzed by UV-VIS spec-troscopy for three samples over a four weeks period. The results were compared to a set of samples exposed, for the fi rst hour, to ON-OFF laser cycles of 10 minutes, moni-tored for the same time range. Samples exposed to short IR light periods showed a signifi cant reduction of the cumulative diffu-sion driven release [ 42 ] compared to the control

(see SI, for full analysis of the release kinetics and Figure S3). The lower diffusivity of the drug in the collapsed network, simi-larly present in other remotely controlled hydrogel systems, [ 43 ] could be exploited to differentiate the time of the drug release from the bead delivery or to modify the kinetics depending on the application. At the same time, the double layer acts as a physical active barrier to hinder or lower the diffusional release of material (cells or drugs) contained inside the alginate beads.

We also tested the possibility of targeted cell-based thera-peutics by encapsulating D1 mouse mesenchymal stem cells (mMSCs) inside magnetic alginate microbeads. The LIVE/DEAD assays showed that cells could be viably encapsulated for at least seven days. Cell viability was higher than 80% after seven days of incubation (see SI and Figure S4). It is likely that cell

of generating multiple types of state-of-the-art magnetic control techniques including fi eld and gradient propulsion, rotating magnetic fi elds, and their combinations. We fi rst demonstrated the real-time, closed-loop servoing of individual magnetic algi-nate beads by implementing a proportional controller (Video S1). Once a bead was selected, the visual tracker was able to recognize it (see blue frame in Figure 3 c); the controller calcu-lated and applied the required magnetic gradients to move the bead along the pre-planned circular trajectory (gray circles in Figure 3 c indicate the target waypoints). Next, we demonstrated automated maneuvering of hydrogel bilayers carrying magnetic microbeads using real-time optical tracking (Figure 3 d). For in vivo applications, a different tracking scheme must be devel-oped that could be based on IR [ 40 ] or magnetic detection [ 41 ] (as

Figure 3. Magnetic manipulation of platforms and NIR activated release of microparticles. a) Encapsulation of magnetic particles inside folding microstructures b) Octomag electromag-netic manipulation system integrated with NIR laser. c) Manipulation of single alginate beads. d) Microrobot manipulation over a selected pattern. The robot follows the preplanned trajec-tory. Red circles denote target destinations and the circles turn into blue as the robot passes over them. e) NIR activated release of microparticles. The scale bars are 200 µ m, 50 µ m and 500 µ m.

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bilayers (see Figure 3 b).

Supporting Information Supporting Information is available from the Wiley Online Library or from the author.

Acknowledgements Financial support by the European Research Council Advanced Grant “Microrobotics and Nanomedicine (BOTMED)”, by the ERC grant agreement n. 247283, and by the Swiss National Science Foundation are gratefully acknowledged. Additionally, this work was supported by the National Institutes of Health (R01 DE0013349).

The authors are thankful to Prof. Dr. Christopher Hierold for his comments and to Simone Schürle for her help with magnetic manipulation experiments. The authors want to acknowledge also Falk Lucas, Stephan Handschin and Dr. Roger Albert Wepf for the assistance in the use of the SEM facilities at EMEZ, ETH Zurich.

Received: August 14, 2013 Published online: November 4, 2013

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viability and proliferative capacity can be greatly improved by modifying alginate with RGD adhesion ligands [ 12 ] and by opti-mizing the cell density at which cells are seeded in the beads. Additionally, because iron oxide limits our ability to visualize cells located more deeply in the interior of individual beads, cell densities/numbers are likely higher than indicated in Figure S4.

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Experimental Section A detailed description of the fabrication of the bilayers, the fabrication of the alginate microbeads, drug release, cytotoxicity and cell viability assays can be found in the Supporting Information.

Characterization of the hydrogel bilayers : swelling ratio and transition temperature of the hydrogels were determined gravimetrically by using gel discs (diameter 4.5 mm, thickness 2 mm), produced by UV polymerization. The gels (a minimum of three per type) were produced and incubated in a water bath (Julabo, Germany) at temperatures ranging from 25 to 55 ° C. At predefi ned time intervals (minimum eight hours to ensure swelling equilibrium), the samples were removed from water, carefully wiped and their weight was recorded. The Equilibrium Swelling Ratio (ESR) at each temperature was defi ned as (Equation ( 1 ):

ESR = Ms ! MdMd

(1)

where M s and M d are the mass of the swollen hydrogel and the dried mass, respectively.

The interior morphology of the hydrogel layers and the dispersion of the graphene oxide in the thermoresponsive one were characterized by Cryo-SEM following a previously assessed protocol (see Supporting Information). [ 21 ]

Characterization of the light sensitivity of hydrogel bilayers : the photo-thermal phase transitions of the nanocomposite layer and of the fi nal double layers were investigated by irradiation using a focused NIR laser (wavelength 785 nm, 1.5 W power, laser spot 5 mm, SLOC lasers, China). Heating of the samples related to time of irradiation was monitored by means of a thermal camera (Flir, USA), until a reference temperature of 60 ° C was reached. Different cycles of excitation and recovery, as well as different power levels (see Figure S5) were recorded to analyze the feasibility of the method.

Experimental Setup : The system consists of eight stationary electromagnets with soft magnetic cores and is capable of producing magnetic fi elds and gradients up to 50 mT and 0.5 T/m at frequencies up to 100 Hz. For visual tracking, a microscope at 6.0 X magnifi cation (Leica M80, Germany) observes the workspace from above. We mounted a NIR laser (wavelength 785 nm, 1.5 W power, laser spot 5 mm, SLOC lasers, China) in a confi guration that allows us to focus the laser beam

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