Photolithographic Patterning of Hydrogels

The union of hydrogel photopolymerization chemistry with photolithographic techniques from the microprocessor industry has enabled the rapid prototyping of hydrogel structures that are uniform in the z-direction but vary in structure or composition in the x- and y-directions. In one method, a cell suspension is mixed with a hydrogel precursor solution and applied to a flat substrate [28, 83, 84]. Illumination of the solution through a mask permits crosslinking only in defined regions. The opaque regions of this photomask block light and inhibit photopolymerization in these shadowed regions while the transparent regions allow light to pass through and initiate hydrogel crosslinking. Simply rinsing the substrate with water removes the uncros-slinked regions, revealing free-standing hydrogel posts containing living cells (Fig. 4.5). It is important to note that although free radical polymerization is a fast chemical process, it is efficiently quenched by atmospheric oxygen and other free radicals. This quenching is believed to prevent the polymerization from extending far into the light-shielded regions on the typical timescales of hydrogel formation, thus providing high contrast at feature edges [85]. An inverse approach involves creating free-standing walls of PEG that form individual wells for the isolation of cells and cell populations. Microwells can be created directly with photolithography using various masking techniques [86, 87]. Research in this area is ongoing to create addressable templates for high throughput screening.

Fig. 4.5 These hydrogel posts were formed using a photolithographic technique. Mixing cells with the precursor solution could allow creation of cell-based microarrays. Photo reprinted by permission from [83]

Photolithography can also be utilized to create two-dimensional patterns of bioactive factors on the surface of hydrogels. This technique utilizes incomplete polymerization of a base hydrogel, leaving free acrylate groups available for further modification. When acrylated bioactive factors are applied to the surface of the hydrogel and illuminated through a photomask, the factors are covalently immobilized to the surface of the hydrogel, as shown in Fig. 4.6 [88]. Iterative replication of this process enables the attachment of multiple factors to the surface of the hydrogel with much lower expense and complication than if the factors were dissolved in the original prepolymer solution. Lower expense is achieved because the bioactive factors need only be applied to the surface of the hydrogel rather than the bulk polymer solution. Additionally, a key advantage of using a hydro-gel for the immobilization of ligands is that unpatterned regions remain highly bioinert while the entire hydrogel is both flexible and compliant.

Rather than utilizing photomasks, liquid crystal display (LCD) projection photolithography utilizes a commercially available LCD projector to cast an image from a computer directly onto the polymer solution to create photo-crosslinked hydrogel structures [89-92]. This technique typically has a feature resolution of 50 mm and sometimes suffers exposure artifacts from the embedded wires used to control each pixel in the LCD [89]. Nevertheless, LCD projectors are inexpensive and can serve as an excellent starting point for exploring the parameters needed for the photolithography of hydrogels.

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