Last winter, researchers at MIT demonstrated a way to generate bar-coded microparticles by the millions. The technique, based on a novel microfluidic device, could provide a way to create millions of labeled tags for medical diagnostics. (See “New Bedside-Diagnostics Tool.”)
Now the researchers have converted the microfluidic fab to turn out particles with precisely structured internal parts. MIT materials scientist Ned Thomas, who co-led the team with MIT chemical engineer Patrick Doyle, says that the new system could increase the sensitivity of the mass-produced diagnostic probes by 10,000-fold. The research is described in the chemistry journal Angewandte Chemie.
In the two-dimensional system invented last year by Doyle, unique biosensor particles are produced by flowing two solutions containing the molecular building blocks for a plastic down a channel one-fifth of a millimeter wide etched into a silicone-polymer block. A pulse of ultraviolet light projected through a stencil stimulates the plastic precursors to solidify into a single particle that’s 50 micrometers across. To turn the particles into biosensors, Doyle’s team doped the plastic solution with a DNA biotag; a series of dots added to the stencil labeled the particles with a pattern visible with a low-magnification microscope.
Subsequently, Thomas and Doyle’s research teams realized that they could use the lithography technique recently developed at the University of Illinois, called phase-mask lithography, to build internal structure into Doyle’s solid particles. Unlike a stencil, which casts a shadow to create a two-dimensional pattern, a phase mask produces a three-dimensional interference pattern. The researchers saw that the transparent block forming the base of Doyle’s microfluidic device could easily double as a phase mask by cutting an undulating pattern into the bottom face of the base. The ultraviolet light needed to activate the polymer precursor is projected up from below and emerges in the microfluidic fab’s flow channel as a blend of beams whose waves are out of phase with one another. Constructive and destructive interference between the beams creates a three-dimensional image within the channel. When the liquid polymer precursor flowing through is exposed to that 3-D image, it solidifies to form a corresponding 3-D plastic structure.
In the work published in Angewandte Chemie, Thomas and Doyle’s team reports producing particles of acrylic plastic 60 micrometers across at a rate of 10,000 per hour. The particles are composed of one-micrometer-wide plastic rods in a square lattice with openings that are roughly two micrometers square. Thomas says that a tighter patterning of the phase mask could narrow the scaffold’s elements to as thin as 200 nanometers, while a smaller stencil could shrink the particles down to 10 micrometers or less.
Thomas says that the 3-D-structured particles have potential to become ultrafast, ultrasensitive biosensors. They’re sensitive because they have plenty of surface area to which DNA or other biotags can attach. With conventional solid microarrays and particles, biotags only adorn the probe’s surface. In contrast, biotags can attach inside the latticework particles, increasing the number of target molecules that bind to a particle, and therefore producing a more intense fluorescent signal. “The particle, of course, is transparent, so if the fluorescence is occurring in the center of the particle, it’s still visible outside,” says Thomas. He adds that he and his team have demonstrated about a 10-fold signal boost so far, and he predicts that they will optimize the lattice to yield at least a 10,000-fold signal boost.
Commercialization of MIT’s microfluidic particle biosensors is by no means around the corner. But several companies have expressed interest in the system, and collaborations are under way to test it on real-world samples from genetic tests. The MIT researchers’ goal is to launch a startup or have licensing agreements in place within two years. Patents are in the works covering the microfluidic process for making particles, its application for making biosensor arrays, and the new phase-mask-enhanced system for structured particles.
Looking beyond biosensors, Thomas envisions applications that dynamically exploit the particles’ mechanical properties. Particles with narrow scaffolding, for example, should be capable of squashing down to squeeze into tight spaces, much as fresh red blood cells squeeze into the tightest capillaries. He also imagines that the latticework particles could beget tunable sieves for handling and sorting much smaller nanoparticles by using polymers that swell and seal up the lattice in response to external conditions such as acidity. “If you were trying to choke off transport of virus particles, for example, this would work nicely,” says Thomas. “That’s one of our dreams.”