David H. Gracias

3D Printed Bionic Ears

The ability to three-dimensionally interweave biological tissue with functional electronics could enable the creation of bionic organs possessing enhanced functionalities over their human counterparts. Conventional electronic devices are inherently two-dimensional, preventing seamless multidimensional integration with synthetic biology, as the processes and materials are very different. Here, we present a novel strategy for overcoming these difficulties via additive manufacturing of biological cells with structural and nanoparticle derived electronic elements. As a proof of concept, we generated a bionic ear via 3D printing of a cell-seeded hydrogel matrix in the precise anatomic geometry of a human ear, along with an intertwined conducting polymer consisting of infused silver nanoparticles. This allowed for in vitro culturing of cartilage tissue around an inductive coil antenna in the ear, which subsequently enables readout of inductively-coupled signals from cochlea-shaped electrodes. The printed ear exhibits enhanced auditory sensing for radio frequency reception, and complementary left and right ears can listen to stereo audio music. Overall, our approach suggests a means to intricately merge biologic and nanoelectronic functionalities via 3D printing.

Self-Propelled Nanotools

We describe nanoscale tools in the form of autonomous and remotely guided catalytically self-propelled InGaAs/GaAs/(Cr)Pt tubes. These rolled-up tubes with diameters in the range of 280-600 nm move in hydrogen peroxide solutions with speeds as high as 180 μm s(-1). The effective transfer of chemical energy to translational motion has allowed these tubes to perform useful tasks such as transport of cargo. Furthermore, we observed that, while cylindrically rolled-up tubes move in a straight line, asymmetrically rolled-up tubes move in a corkscrew-like trajectory, allowing these tubes to drill and embed themselves into biomaterials. Our observations suggest that shape and asymmetry can be utilized to direct the motion of catalytic nanotubes and enable mechanized functions at the nanoscale.

Tetherless thermobiochemically actuated microgrippers

We demonstrate mass-producible, tetherless microgrippers that can be remotely triggered by temperature and chemicals under biologically relevant conditions. The microgrippers use a self-contained actuation response, obviating the need for external tethers in operation. The grippers can be actuated en masse, even while spatially separated. We used the microgrippers to perform diverse functions, such as picking up a bead on a substrate and the removal of cells from tissue embedded at the end of a capillary (an in vitro biopsy).

Self-folding polymeric containers for encapsulation and delivery of drugs

Self-folding broadly refers to self-assembly processes wherein thin films or interconnected planar templates curve, roll-up or fold into three dimensional (3D) structures such as cylindrical tubes, spirals, corrugated sheets or polyhedra. The process has been demonstrated with metallic, semiconducting and polymeric films and has been used to curve tubes with diameters as small as 2nm and fold polyhedra as small as 100nm, with a surface patterning resolution of 15nm. Self-folding methods are important for drug delivery applications since they provide a means to realize 3D, biocompatible, all-polymeric containers with well-tailored composition, size, shape, wall thickness, porosity, surface patterns and chemistry. Self-folding is also a highly parallel process, and it is possible to encapsulate or self-load therapeutic cargo during assembly. A variety of therapeutic cargos such as small molecules, peptides, proteins, bacteria, fungi and mammalian cells have been encapsulated in self-folded polymeric containers. In this review, we focus on self-folding of all-polymeric containers. We discuss the mechanistic aspects of self-folding of polymeric containers driven by differential stresses or surface tension forces, the applications of self-folding polymers in drug delivery and we outline future challenges.

Fabrication of Micrometer‐Scale, Patterned Polyhedra by Self‐Assembly

We recently proposed and demonstrated a strategy for fabricating self-assembling, three-dimensional (3D) electrical networks. In this demonstration, we used millimeter scale building blocks (polyhedra) whose faces were patterned with copper connectors and devices (light-emitting diodes). One significant hurdle to implementing self-assembly in practical systems is that of miniaturizing the assemblies. To do so would require us to construct building blocks similar to those of ~1 mm scale, but on the micrometer scale. The building blocks must have the following characteristics: a) polyhedral structures, b) faces patterned with arbitrary patterns that would serve as connectors, and c) microelectronic devices attached to the faces of the polyhedron. It is difficult to fabricate micrometer scale polyhedral structures. Structures with these dimensions are usually fabricated by projection lithography, and this technique is inherently planar. Most methods of fabrication in 3D utilize processes such as surface micromachining that are precise and versatile, but also expensive and limited in the range of materials that can be used and the types of structures that can be generated. It is also difficult to generate arbitrarily patterned structures in 3D or on curved surfaces. Techniques for patterning have been limited to microcontact printing, projection lithography on spherical substrates using elaborate optics, and shell plating onto die-cast mandrills. Fabricating devices on 3D objects is extremely difficult; this is because processes (e.g., ion implantation) used to build silicon-based microdevices are inherently planar techniques. This paper describes the fabrication of patterned polyhedra, having 100±300 lm sides, by the spontaneous folding of two-dimensional (2D) structures under the influence of the surface tension of liquid solder. Our examination of this approach was stimulated by the early work of Pister and Shimoyama on micromachined hinges and by the extensive research of Syms and others on the use of capillary forces in liquid solder and similar methods for directly shrinking polymer joints for the assembly of non-planar microstructures. The structures we describe can be patterned and processed in 2D using conventional techniquesÐphotolithography, evaporation, electrodeposition, etchingÐthat have been extensively developed by the semiconductor industry. In the past, auto-folding has been used primarily to actuate micrometer scale components in microelectromechanical systems (MEMS) devices. In our work, we demonstrate that the self-assembling process of auto-folding can be used as a strategy for fabricating patterned 3D components from 2D precursors. We have also demonstrated that it is possible to build 3D polyhedra whose faces contain single crystal silicon chipsÐthe most primitive electronic device, i.e., a resistor. The approach we demonstrate has four steps: 1) The desired structures are designed in planar form as a series of unconnected but adjacent faces. 2) The faces are fabricated in 2D on a sacrificial layer using a combination of photolithography, evaporation, etching, and electrodeposition. 3) The ensemble of faces is covered with a thin film of liquid solder by dip coating. 4) The structure is released from the substrate by dissolving the sacrificial layer, and allowed to fold under the influence of the surface tension of the molten solder. This strategy is sketched in Figure 1. We experimented with many different materials, structures, and processes. Figure 2 shows scanning electron microscopy (SEM) images of folded metallic polyhedra and the 2D precursors of these structures. The metallic faces of the polyhedra contained either holes (the trigonal pyramid in Fig. 2) or solid faces (as seen in the tetragonal pyramid, cube, and hexagonal prism). The faces ranged in size between 100±300 lm (on a side). The 2D precursors contained faces that were not hinged; the faces were aligned as close to each other as possible (given the mask and photolithographic capabilities). For 200±300 lm faces, spacings between 8 and 15 lm worked well; for 100 lm faces, a spacing of 8 to 10 lm was required. When the 2D structures were dipped in solder, the solder bridged the faces and formed a continuous layer. The 2D precursors were released from the wafer by dissolving a sacrificial layer on which they were built. The precursors were heated above the melting point of the solder. The liquid solder tried to minimize its surface area (capillarity); this process drew the faces together to form a compact 3D polyhedron. The equilibrated 3D polyhedron was, at this point, filled with solder; the folding thus worked best when the volume of the solder present was equal to the volume of the polyhedron. Since the volume of solder present was equal to that deposited on the 2D precursor, the critical step controlling the yield of the process was the deposition of solder. We controlled the amount of solder deposited by changing the surface tension of the liquid solder, as well as by changing the solder±copper interfacial energy. The surface tension of liquids decreases approximately linearly with increasing temperatures; as a result, when the solder dip-coating was carried out at elevated temperatures (100 C for a solder with melting point, m.p., 47 C), a smaller volume of solder was deposited. The solder± copper interfacial energy was also controlled using fluxes and acids that aid in cleaning organic contaminants and dissolving oxide layers at the solder and copper surfaces. When the con-

Differentially photo-crosslinked polymers enable self-assembling microfluidics

An important feature of naturally self-assembled systems such as leaves and tissues is that they are curved and have embedded fluidic channels that enable the transport of nutrients to, or removal of waste from, specific three-dimensional regions. Here we report the self-assembly of photopatterned polymers, and consequently microfluidic devices, into curved geometries. We discover that differentially photo-crosslinked SU-8 films spontaneously and reversibly curve on film de-solvation and re-solvation. Photolithographic patterning of the SU-8 films enables the self-assembly of cylinders, cubes and bidirectionally folded sheets. We integrate polydimethylsiloxane microfluidic channels with these SU-8 films to self-assemble curved microfluidic networks.

Self-folding devices and materials for biomedical applications

Because the native cellular environment is 3D, there is a need to extend planar, micro- and nanostructured biomedical devices to the third dimension. Self-folding methods can extend the precision of planar lithographic patterning into the third dimension and create reconfigurable structures that fold or unfold in response to specific environmental cues. Here, we review the use of hinge-based self-folding methods in the creation of functional 3D biomedical devices including precisely patterned nano- to centimeter scale polyhedral containers, scaffolds for cell culture and reconfigurable surgical tools such as grippers that respond autonomously to specific chemicals.

Self-folding thermo-magnetically responsive soft microgrippers.

Hydrogels such as poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAM-AAc) can be photopatterned to create a wide range of actuatable and self-folding microstructures. Mechanical motion is derived from the large and reversible swelling response of this cross-linked hydrogel in varying thermal or pH environments. This action is facilitated by their network structure and capacity for large strain. However, due to the low modulus of such hydrogels, they have limited gripping ability of relevance to surgical excision or robotic tasks such as pick-and-place. Using experiments and modeling, we design, fabricate, and characterize photopatterned, self-folding functional microgrippers that combine a swellable, photo-cross-linked pNIPAM-AAc soft-hydrogel with a nonswellable and stiff segmented polymer (polypropylene fumarate, PPF). We also show that we can embed iron oxide (Fe2O3) nanoparticles into the porous hydrogel layer, allowing the microgrippers to be responsive and remotely guided using magnetic fields. Using finite element models, we investigate the influence of the thickness and the modulus of both the hydrogel and stiff polymer layers on the self-folding characteristics of the microgrippers. Finally, we illustrate operation and functionality of these polymeric microgrippers for soft robotic and surgical applications.

Biopsy with Thermally‐Responsive Untethered Microtools

Thermally activated, untethered microgrippers can reach narrow conduits in the body and be used to excise tissue for diagnostic analyses. As depicted in the figure, the feasibility of an in vivo biopsy of the porcine bile duct using untethered microgrippers is demonstrated.

Thin Film Stress Driven Self-Folding of Microstructured Containers**

Lithography, the workhorse of the microelectronics industry,is routinely used to fabricate micro and nanostructures in ahighly monodisperse manner, with high accuracy and preci-sion. However, one of the central limitationsof this technologyis that it is inherently two-dimensional (2D) as a result of thewafer-based fabrication paradigm. It is extremely challengingto fabricate three-dimensional (3D) patterned structures, letalone complex structures containing encapsulated objects, onthe sub-mm scale. Thus, the parallel fabrication of such struc-tures remains a major challenge that needs to be addressed.Some solutions have emerged that enable sub-mm-scalelithographic fabrication in 3D; these include techniques suchas wafer stacking,