2.2.1. Template design and production

First, the lithographic template is generated, which contains feature patterns that determine the size and shape of the particles to be synthesized (I). In imprint lithography, the lithographic template is a patterned mold, typically polymeric in nature, with negative features corresponding to the particles to be synthesized and which is prepared from a master template [43]. Imprint lithography of hydrogel colloids has developed as an extension of standard soft lithography techniques originally used for the production of patterned polymeric substrates such as microfluidic devices [44]. The first process to demonstrate imprint lithography of individual hydrogel colloids was the particle replication in non-wetting templates (PRINT) method developed by Desimone and co-workers [34]. Similar processes and variations have been presented in the literature [24] and [45]. In recent years, these processes have enjoyed significant enhancements in performance due to advances in microfabrication technology. For example, improved resists and write methods for master templates have enabled the generation of two- and three-dimensional patterns with feature sizes below 100 nm [46]. Furthermore, the ability to form template patterns from any free-standing object has led to the interesting ability to template various nanoscale objects and thus replicate them in the form of hydrogel colloids [47]. Unfortunately, the complexity of the hydrogel colloids generated by imprint lithography is constrained by practical limitations in the production of soft templates. Bending and buckling of the lithographic template, for instance, limit the transfer of patterns with high-aspect ratios or internal features [48].

In photolithography and flow lithography, the template is light (or other radiation) incident on the material to be synthesized, which has been patterned through various optical elements. As a result, the minimum feature size for photolithography is limited by the wavelength of the light used in the diffraction-limiting case. Typically, the light source used is the same as that used to initiate photopolymerization, such that pattern transfer and hydrogel synthesis occur simultaneously. Common processes for photolithographic hydrogel synthesis use transparency masks to pattern the incident light. In most cases, this approach limits the morphology of the structures formed to two-dimensional extruded shapes, where the thickness of the particle is determined by the height of the fluid that is exposed to the patterned light. However, more recent studies have demonstrated the ability to form nearly arbitrary three-dimensional hydrogel structures through photolithography, by three-dimensional projection of patterned light with multi-photon [42] and [49], interference pattern [50], or holographic [51] and [52] sources. Alternatively, three-dimensional features can be achieved by pre-forming the hydrogel precursor into a three-dimensionally patterned or flexible mold [53] and [54], essentially combining the capabilities of photolithography with imprint lithography. Photolithographic techniques feature several attractive characteristics not offered by imprint lithography. For example, the design and preparation of light-patterning elements such as transparency masks are significantly less resource-intensive than microfabrication. In addition, recent variations have used digital micromirror devices (DMDs) in place of transparencies, resulting in the ability to dynamically change the template pattern during processing, as well as create highly complex and interconnected shapes [25], [40] and [55] not achievable using imprint lithography.

2.2.2. Loading of hydrogel pre-cursor

Once the lithographic template is prepared, the hydrogel pre-cursor is introduced into a reservoir that is aligned coincident with the lithographic template (II). For imprint lithography, the fluid reservoir is often the negative pattern features of the template itself, which is drop-filled either manually or automatically into the polymer mold [45]. Unfortunately, this approach often results in poor transfer of the template pattern to the hydrogel particles due to a non-uniform filling. To prevent this, other methods use a fluid film that is cast onto a planar substrate [34]. The fluid film is then sandwiched between the planar substrate and soft template, the latter of which is filled by capillary forces [24] and [26]. A major advance introduced by the PRINT technique is the utilization of perfluoropolyether (PFPE) soft templates and substrates, which are highly non-wetting to both polar and non-polar organic solvents. This allows for the filling of multiple immiscible fluid layers within the template, thereby producing chemically anisotropic particles with simple shapes [26].

The simplest photolithographic methods involve pattern transfer into a stationary fluid film or reservoir [29], [42] and [56] prepared in a manner similar to that used in imprint lithography. Recently, a number of so-called “flow lithography” techniques have been introduced, in which photolithography is performed in situ within a microfluidic environment [23]. Initial iterations of flow lithography involved the continuous flow of the hydrogel precursor within a microfluidic channel, which was exposed at regular intervals to ultraviolet (UV) light patterned by a photomask to produce discrete particles [57]. Because of the interplay between polymerization and flow, this resulted in poor transfer of pattern features to the synthesized particles. This shortcoming led to the development of stop-flow lithography (SFL), in which the flow of precursor is stopped prior to a patterned exposure, resulting in more precise pattern transfer for feature sizes approaching 1 μm [23] and [58].

Flow lithography involves the introduction of easily manipulated laminar microflows into photolithographic processing. As such, flow lithography techniques such as stop-flow lithography (SFL) [23] and optofluidic maskless lithography [25] have led to a number of new motifs of hydrogel colloid synthesis previously unavailable using droplet-based microfluidic techniques [59]. For instance, the ability to create co-flowing layered streams allows for the facile production of hydrogels with multiple polymer chemistries on the same particle of arbitrary one-dimensional configuration [23]. Unlike imprint lithography, the different polymer chemistries need not be immiscible, providing for nearly arbitrary multi-functionality. Furthermore, if the co-flowing precursor streams are immiscible, the interfacial tension between the fluids can be used to induce three-dimensional curvature to the particle shape [60]. Initial studies were limited to co-flowing streams in the plane of the pattern transfer, lowering throughput and limiting chemical anisotropy to “striped” particles [31]. However, by stacking the different chemical layers vertically with respect to the incident irradiation, these limitations can be avoided, allowing for synthesis of particles with more complex designs of chemical “patchiness” [61]. As mentioned previously, the geometry of the microchannel in which the flow lithography is performed can also be adjusted in order to impart three-dimensional features to the hydrogel particles [40] and [53]. Combined with the ability to alternate the flow of different precursor streams, this design strategy can be leveraged to impart highly sophisticated chemical patterns to a single hydrogel particle [53].

2.2.3. Polymerization and cross-linking

After aligning the fluid with the template features, the polymerization reaction is initiated (III), resulting in the formation of cross-linked particle structures within the fluid. In the common case of photopolymerization, this is done by exposure of the fluid to a light source for a pre-defined period of time dictated by the polymerization kinetics. This requires the fluid, fluid reservoir, and/or template to be transparent to the required wavelength(s) of radiation. Typically, the fidelity with which the patterned template features are transferred to the synthesized polymer structure depends critically on several factors relating to the polymerization kinetics and mass transport within the precursor fluid. In photolithography processes, the rate of diffusion of reacting species relative to the rates of propagation and termination defines the lower limit of the feature resolution [62]. Furthermore, the presence and transport of polymerization-quenching species such as oxygen will provide further limitations on the fidelity of pattern transfer, although such inhibition provides a particularly important role in flow lithography techniques, as it prevents the adhesion of particles to the microfluidic device walls [62].

2.2.4. Particle recovery

After the polymerization has completed (or is quenched), the particles are then recovered from the fluid reservoir (IV). This final step is often difficult in practice, as the newly synthesized particles can adhere to the template and/or fluid reservoir depending on the surface chemistry and wetting properties of the materials used, as well as the way in which the fluid is filled. In the case of imprint lithography, there is often a residual polymerized film which connects adjacent particles that must be eliminated before isolated particles can be recovered [24]. First, the particles and so-called “flash layer” are isolated from the patterned mold, typically by mechanical delamination. The flash layer is then eliminated by various physical or chemical means such as wet or dry etching [24]. In the case of the PRINT method and its variations, careful design of the mold chemistry results in a fluid seal which prevents the formation of a flash layer [34]. Even so, difficulties arise in removing newly formed particles from their mold features. More recent iterations of the PRINT method harvest particles from the mold by adhering a polymer that is wetting to the hydrogel particles but not to the PFPE mold, which is then used to mechanically delaminate the particles from the mold. Subsequent agitation of the adhesive allows for the recovery of the particles [22]. In other cases, the mold material was cleverly chosen such that it can be dissolved or swollen in order to remove the synthesized hydrogel colloids [45].

Since photolithographic techniques do not require the contact of the precursor fluid with the patterned photomask, particle recovery is much simpler than for imprint lithography. For stationary photolithography, the newly formed hydrogel particles can simply be washed from the film or fluid reservoir, provided that the precursor is non-wetting and the hydrogel does not adhere to the substrate. This can be ensured through a proper choice of substrate chemistry [56]. In the case of flow lithography techniques, the presence of flow is advantageous in that the newly formed hydrogel particles can be freely advected away from the region of synthesis. Other specific features of conventional microfluidic fabrication and operation can also aid in particle recovery. As mentioned previously, in SFL, oxygen-induced inhibition of the polymerization reaction is heightened near the walls for oxygen-permeable materials such as poly(dimethylsiloxane) (PDMS) [62], thereby preventing newly formed hydrogel particles from adhering to the synthesis channel walls. In the case of hydrodynamic focusing lithography (HFL), the ability to co-flow non-polymerizable fluid layers between the particles and the channel walls enables the use of oxygen-impermeable microfluidic materials of construction such as glass [61]. For cases in which the microfluidic synthesis channel has three-dimensional features that are polymerized into or around, the particles can either be held in place in order to perform additional synthesis steps, or can be released upon the application of a pressure drop capable of deforming the microchannel [53] and [63].

Polymeric materials synthesized by lithography-based processes typically require some form of purification after recovery in order to remove unreacted material or other impurities left over from the synthesis process. For hydrogel colloids, this is typically accomplished through a solvent exchange in which the particles receive several “washes” against a desired final suspending medium. Isolation of the particles during these wash steps can be aided by centrifugation, filtration, or magnetic separation [38]. However, since hydrogel materials are soft by nature, the conditions under which purification is performed must be carefully chosen to ensure that the hydrogel colloids are not adversely affected by extreme shear or compression. In the case of microfluidic-based flow lithography techniques, the particles can be transported and manipulated downstream under gentle laminar flow conditions, allowing for facile additional processing in situ after synthesis, such as purification [64], functionalization [65], or assembly [66].

2.2.5. Process throughput

The utility and eventual commercialization of particle synthesis technologies depend critically on process throughput and yield, as well as operating cost. Since traditional soft lithography techniques are now fairly routine, both imprint lithography and microfluidic-based flow lithography of hydrogel colloids present a minimal expense relative to material costs. However, because of limitations on contemporary microfabrication, both techniques have suffered from fairly low throughput. Imprint lithography suffers due to limitations on the size of molds that can be prepared from typical soft lithography methods. For example, the first demonstrations of the PRINT method reported throughputs on the order of several milligrams per hour of material [34]. Significant progress has been made recently in scaling up the process, which can now be performed via roll-to-roll processing with throughputs on the order of ten grams of material per hour [22]. In the case of photolithography, the primary limiting factor is the available field of irradiation. Since most photolithography-based processes to produce colloidal hydrogels are based on optical projection, throughput is limited to the field of view of the objective used

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