Researchers at Yonsei University in Seoul developed a 3D printed microcolumn array designed to produce sub-nanomole quantities of DNA per feature while maintaining dense synthesis layouts. Published in Scientific Reports (Nature Portfolio), the study describes a substrate fabricated using LCD-based vat photopolymerization that combines aspects of planar oligonucleotide arrays and column-based DNA synthesis. Each device can be produced in roughly 2.5 hours with an estimated material cost of about $0.12.
Oligonucleotide libraries support applications in synthetic biology, genomics, and DNA data storage. Planar synthesis platforms generate large numbers of sequences simultaneously but typically produce femtomole-scale quantities per feature because reactions occur on flat surfaces with limited reaction volume. Column-based synthesis systems that use controlled pore glass (CPG) beads operate in three-dimensional reaction environments and generate nanomole- or micromole-scale quantities per sequence but support far fewer parallel reactions. Work from the Seoul chemistry team integrates these approaches by arranging bead-filled microcolumns within a dense printed array.
Each substrate contains columns positioned in a grid separated by several hundred micrometers. A square opening at the top allows insertion of CPG beads, while a narrow slit at the bottom prevents bead escape while allowing reagent flow. Bulk reagents spread across the array surface and are drawn through the columns using vacuum suction. Sequence-specific phosphoramidites are delivered through an inkjet deposition system according to the synthesis sequence. Hydrophobic surfaces surrounding the wells contrast with the hydrophilic CPG beads inside the columns, encouraging droplets to enter the microcolumns rather than spread across the substrate and reducing the risk of overflow between neighboring synthesis sites.
Fabrication relied on a Sonic Mini 8K LCD printer manufactured by Phrozen, a producer of desktop stereolithography systems. Researchers screened eight commercial photopolymer resins for chemical resistance to reagents used in oligonucleotide synthesis, including dichloroacetic acid, acetonitrile, oxidizers, propylene carbonate, and aqueous ammonia. Test samples remained immersed in these reagents for twenty-four hours. Several materials exhibited swelling, cracking, or structural deformation during testing. Three resins showed less than two percent weight change after exposure. A formulation known as Deep Blue demonstrated the most stable performance and was selected for fabrication.
After selecting the material, researchers optimized printing parameters to create openings capable of retaining CPG beads measuring roughly 70 to 150 micrometers in diameter. Sudan Orange G was added to the resin as a UV absorber to limit excess polymerization caused by light scattering during exposure. Printing conditions were adjusted by reducing UV intensity, setting layer thickness to 50 micrometers, and tuning exposure time to achieve stable microhole formation. A smooth black glass build plate replaced the patterned metal plate typically used in resin printers, reducing reflected light that previously caused over-curing in the initial printed layer.
These adjustments enabled consistent fabrication of rectangular microholes capable of retaining CPG beads while allowing reagent flow. Each finished substrate measures approximately 25 by 33 millimeters and contains 1,000 microcolumns spaced 550 micrometers apart. This layout allows approximately 324 columns within one square centimeter. Printing requires about thirty minutes followed by a two-hour post-curing stage, and multiple substrates can be produced simultaneously.
Researchers evaluated synthesis performance using an inkjet-based phosphoramidite DNA synthesis system previously developed by the group. Columns loaded with CPG beads underwent repeated reagent delivery cycles to synthesize a 15-base poly(dT) oligonucleotide. Urea-PAGE analysis confirmed formation of the expected full-length product together with shorter sequences resulting from incomplete coupling reactions. Image analysis indicated that the full-length product represented roughly 60.7 percent of the signal, corresponding to an estimated stepwise coupling efficiency of approximately 96.23 percent.
Total DNA recovered from the array measured about 705,513 nanograms. Assuming uniform synthesis across the device, this corresponds to roughly 155 picomoles per column. Output at this scale exceeds femtomole-level yields typical of planar synthesis arrays by several orders of magnitude while maintaining dense feature layouts.
Remaining limitations require further investigation. Coupling efficiency remains lower than values commonly reported for commercial DNA synthesizers, which often exceed 99 percent per step. Researchers note that reagent flow, incomplete washing, or constraints within the custom synthesis system may influence performance. Future work using next-generation sequencing could map synthesis variability across individual microcolumns and verify spatial uniformity of the process.
The work from Yonsei’s research team provides a proof-of-concept demonstrating that vat photopolymerization can produce microreactor arrays suitable for biochemical synthesis using widely available hardware. Similar bead-based reactions used in RNA or peptide synthesis could potentially operate within the same microcolumn architecture using different functionalized supports.
Titled “Fabrication of microcolumn arrays for high-throughput oligonucleotide synthesis using 3D printing,” the study was conducted by Haeun Kim, Junhyeong Kim, and Duhee Bang from the Department of Chemistry at Yonsei University, with Bang serving as the corresponding author.
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Featured image shows Optimization of UV exposure time for microscale hole 3D printing. Image via PubMed Central.
