Despite the fact that we live in a three-dimensional (3D) world and macroscale engineering is 3D, conventional sub-mm scale engineering is inherently two-dimensional (2D). New fabrication and patterning strategies are needed to enable truly three-dimensionally-engineered structures at small size scales. Here, we review strategies that have been developed over the last two decades that seek to enable such millimeter to nanoscale 3D fabrication and patterning. A focus of this review is the strategy of self-assembly, specifically in a biologically inspired, more deterministic form known as self-folding. Self-folding methods can leverage the strengths of lithography to enable the construction of precisely patterned 3D structures and “smart” components. This self-assembling approach is compared with other 3D fabrication paradigms, and its advantages and disadvantages are discussed.

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 (3D) regions. Here, we report the self-assembly of photopatterned polymers, and consequently microfluidic devices, into curved geometries. We discovered that differentially photo-crosslinked SU-8 films spontaneously and reversibly curved upon film de-solvation and re-solvation. Photolithographic patterning of the SU-8 films enabled the self-assembly of cylinders, cubes, and bidirectionally folded sheets. We integrated polydimethylsiloxane (PDMS) microfluidic channels with these SU-8 films to self-assemble curved microfluidic networks.

We demonstrate a methodology that utilizes the specificity of enzyme-substrate biomolecular interactions to trigger miniaturized tools under biocompatible conditions. Miniaturized grippers were constructed using multilayer hinges that employed intrinsic strain energy and biopolymer triggers, as well as ferromagnetic elements. This composition obviated the need for external energy sources, and allowed for remote manipulation of the tools. Selective enzymatic degradation of biopolymer hinge components triggered closing of the grippers; subsequent reopening was achieved with an orthogonal enzyme. We highlight the utility of these enzymatically triggered tools by demonstrating the biopsy of liver tissue from a model organ system and gripping and releasing an alginate bead. This strategy suggests an approach for the development of smart materials and devices that autonomously reconfigure in response to extremely specific biological environments.

We demonstrate mass-producible, mobile, self-loading microcontainers that can be used to encapsulate both non-living and living objects, thus forming three-dimensionally patterned, mobile microwells.Studies of cells and their function have traditionally been performed on two-dimensional (2D) cell cultures. However, the omission of the third dimension can greatly impact cell behavior by limiting interactions with the surroundings. 1 Microwells in substrates have been developed to address this, but are typically accessible only from one interface; this limitation is especially pronounced in cell culture when the encapsulated cells may experience nutrient deficient conditions due to well geometry and size. 2Researchers continue to add new functionality to microwells, such as making them compatible with high resolution analysis, adding networking channels to facilitate cell-cell interactions, integrating stimulation/measurement devices, and devising methods to generate dense arrays of wells with individually customizable, variable geometry morphologies. 3,4 Also, microwell structures for bioreactors have been designed with porous membrane floors that allow for media perfusion through the well. 5 This allows media to convectively enter the microwell from one interface and exit through another. However, despite the advancements in technology, current microwells essentially only provide a quasi-3D environment, where patterning is limited to 2D and cells are in contact with planar surfaces. 3 Truly 3D encapsulation, where porosity is precisely engineered on all faces in 3D, allows for greater interaction between encapsulated cells and surrounding media.In this communication, we describe photolithographically structured, mobile microcontainers that function like three-dimensionally patterned, mobile microwells. The containers load themselves as they self-assemble from cruciform templates en masse at around 40°C, a temperature low enough to enable parallel loading of biological objects. These containers have porous surfaces and interact with their surroundings in all three dimensions. Additionally, the untethered nature of the cruciforms and containers, coupled with the use of ferromagnetic materials, allows for remote-controlled guidance of both unloaded cruciforms as well as loaded containers. 7 The assembly of the microcontainers is thermally triggered, without the need for any external connections. Photolithography enables the containers to be fabricated with precisely-engineered monodisperse sizes, shapes, and wall porosity. 6 Using self-assembly, 2D templates are transformed into 3D structures with porosity in all dimensions. We demonstrate the self-loading of glass beads, L929 fibroblast cells, and Triops embryos. The loading of biological contents highlights the utility of the low temperature self-loading process.Fabrication of the microcontainers was based on stress-driven assembly using thin film hinges and has been described in detail elsewhere. 8 Briefly, the microcontainers were constructed as 2D cru...

Nature utilizes self-assembly to fabricate structures on length scales ranging from the atomic to the macro scale. Self-assembly has emerged as a paradigm in engineering that enables the highly parallel fabrication of complex, and often three-dimensional, structures from basic building blocks. Although there have been several demonstrations of this self-assembly fabrication process, rules that govern a priori design, yield and defect tolerance remain unknown. In this paper, we have designed the first model experimental system for systematically analyzing the influence of geometry on the self-assembly of 200 and 500 µm cubes and octahedra from tethered, multi-component, two-dimensional (2D) nets. We examined the self-assembly of all eleven 2D nets that can fold into cubes and octahedra, and we observed striking correlations between the compactness of the nets and the success of the assembly. Two measures of compactness were used for the nets: the number of vertex or topological connections and the radius of gyration. The success of the self-assembly process was determined by measuring the yield and classifying the defects. Our observation of increased self-assembly success with decreased radius of gyration and increased topological connectivity resembles theoretical models that describe the role of compactness in protein folding. Because of the differences in size and scale between our system and the protein folding system, we postulate that this hypothesis may be more universal to self-assembling systems in general. Apart from being intellectually intriguing, the findings could enable the assembly of more complicated polyhedral structures (e.g. dodecahedra) by allowing a priori selection of a net that might self-assemble with high yields.