  Solid-phase synthesis techniques underpin the synthesis of DNA,
oligopeptides, oligosaccharides, and combinatorial libraries for drug
discovery. State-of-the-art solid-phase synthesizers can produce
oligonucleotides up to 200-300 nucleotides while using excess reagents.
Accumulated errors over multiple reaction cycles prevent the synthesis of
longer oligonucleotides for the genome scale engineering of synthetic
biological systems. The sources of these errors in synthesis columns remains
poorly understood. Here we show that bead-bead stacking significantly
contributes to reaction errors in columns by analyzing enzymatic coupling of
fluorescently labelled nucleotides onto the initiated beads along with
porosity, particle tracking and diffusion calculations. To circumvent stacking,
we introduce dielectrophoretic bead-droplet reactor (DBDR); a novel approach to
synthesize on individual microbeads within microdroplets. Dielectrophoretic
force overcomes the droplet-medium interfacial tension to encapsulate and eject
individual beads from microdroplets in a droplet microfluidic device. Faster
reagent diffusion in droplets, and non-uniform electric field induced
enhancement in reagent concentration at its surface can improve reaction
fidelities in DBDR. Fluorescence comparisons suggest around 3-fold enhancement
of reaction fidelity compared to columns. DBDR can potentially enable the
high-purity synthesis of arbitrarily long strands of DNA to meet the emerging
demands in healthcare, environment, agriculture, materials, and computing.
